Metrics details An Author Correction to this article was published on 17 January 2025 This article has been updated De novo drug design aims to generate molecules from scratch that possess specific chemical and pharmacological properties We present a computational approach utilizing interactome-based deep learning for ligand- and structure-based generation of drug-like molecules This method capitalizes on the unique strengths of both graph neural networks and chemical language models offering an alternative to the need for application-specific reinforcement It enables the “zero-shot" construction of compound libraries tailored to possess specific bioactivity In order to proactively evaluate the deep interactome learning framework for protein structure-based drug design potential new ligands targeting the binding site of the human peroxisome proliferator-activated receptor (PPAR) subtype gamma are generated The top-ranking designs are chemically synthesized and computationally Potent PPAR partial agonists are identified demonstrating favorable activity and the desired selectivity profiles for both nuclear receptors and off-target interactions Crystal structure determination of the ligand-receptor complex confirms the anticipated binding mode This successful outcome positively advocates interactome-based de novo design for application in bioorganic and medicinal chemistry enabling the creation of innovative bioactive molecules \({{{{{{\mathcal{G}}}}}}}=\left({{{{{{\mathcal{V}}}}}}},{{{{{{\mathcal{E}}}}}}},{{{{{{\mathcal{R}}}}}}}\right)\) where \({{{{{{\mathcal{G}}}}}}}\) denotes the graph \({{{{{{\mathcal{E}}}}}}}\) edges and \({{{{{{\mathcal{R}}}}}}}\) the position in 3D space All protein atoms farther away than 5 Å from any atom of the bound ligand were removed yielding a pocket-centric representation of the binding pocket d The ligands are represented as two-dimensional (2D) graphs \({{{{{{\mathcal{G}}}}}}}=\left({{{{{{\mathcal{V}}}}}}},{{{{{{\mathcal{E}}}}}}}\right)\) the node features within the graph are updated through a message passing process This can be done using either 2D or 3D message passing depending on the nature of the molecular representation As a result of the subsequent pooling process which captures the essential characteristics and representations of the molecule This condensed representation provides a compact encoding of the molecule’s features The latent space vector can be optionally concatenated with a wishlist of desired physicochemical properties for the output molecule This allows for the incorporation of project-specific property constraints or objectives in the de novo molecular design process and LSTM refers to a type of RNN with Long Short-Term Memory cell architecture f Workflow of the presented study including DRAGONFLY validation DRAGONFLY application to peroxisome proliferator-activated receptor (PPAR) chemical synthesis and biological characterization and FEP denotes Free Energy Perturbation calculations The selection of the graph-to-sequence architecture was made to facilitate the development of deep learning models capable of supporting both ligand-based and structure-based molecular design focusing on five selected drug targets related to nuclear hormone receptors Each plot displays a horizontal line representing the mean absolute deviation (MAD) of the training data The error bars on the plots represent the standard deviation observed during a 10-fold cross-validation Source data are provided as a Source Data file These findings underscore the effectiveness of utilizing a combination of descriptors These results suggest that DRAGONFLY is not limited to recapitulating the training data but also has the capacity to explore and generate molecules in previously uncharted regions of chemical space albeit the extent of this exploration warrants further investigation the use of the two chemical alphabets resulted in comparable numbers of molecules that were predicted to fulfill all desired properties Because of the better performance of the SMILES-based models for the objectives of synthetic accessibility and desired physical and chemical properties we used these models in the prospective study The plot displays the quantitative structure-activity relationship (QSAR) score representing the predicted binding affinity to PPARγ against the novelty score The desired region for the generated molecules novelty and the predicted bioactivity requirements is highlighted by a blue box located in the upper right corner of the plot b Molecular structures of the top-ranking de novo designs The predicted quality of the molecules decreases progressively from top to bottom The ranking criteria were PPARγ + PPARδ dual-target affinity and structural novelty (left or PPARγ single-target affinity and structural novelty (right Molecule 9 ranks among the top five molecules on both lists c Examples of non-carboxylic head groups and secondary amides from the top-100 molecules ranked for PPARγ where the gray shaded R group represents an aromatic moiety connected to a linker These alternative head groups demonstrate the structural diversity and potential for exploring different chemistries and bioisosters in the design of novel molecules within the top-ranked subset Both ligands exhibited lipophilicity values within the range of 1–2 (logD1: 1.5 2: 1.7) which falls within the preferred range for orally administered drugs and is comparable to the logD value of aleglitazar (logD: 1.4) the computer-designed compounds 1 and 2 showcase a promising drug-like profile signifying substantial potential for advancement in further drug development Crystal structure complex of the ligand-binding domain of human nuclear receptor PPARγ and compound 1 (a) Illustration of the asymmetric unit containing two protein molecules Refined cartoon structure of the complex showing compound 1 (stick model in blue) bound to chain A and chain B empty (chain A on the right and chain B on the left) (b) Close-up view of the binding pose of compound 1 (blue) with hydrogen bonds to residues Tyr473 and Ser289 as well as a water-mediated hydrogen bond to His449 shown as dashed lines (PDB-ID: 8PBO) The black arrowhead marks the entry to the binding pocket of the receptor certain protein residues have been omitted from the illustration The generative deep learning method referred to as DRAGONFLY was evaluated in the context of ligand-based and structure-based molecular design tasks The collective results specifically highlight the success of structure-based de novo design of potent partial agonizts for PPARγ These molecules effectively interact with the receptor in a canonical binding mode while also demonstrating the desired selectivity towards the receptor and favorable ADME properties By leveraging an interactome-based deep learning approach and employing a graph-to-sequence neural network architecture DRAGONFLY addresses certain challenges commonly encountered in generative molecular design methods This approach demonstrated to (i) achieve similar or even superior results compared to a respectively fine-tuned RNN-based CLM for drug-like ligand templates (ii) enable structure-based design using 3D protein binding sites and (iii) effectively incorporate desired physical and chemical properties into the generated molecules Its ability to combine structure-based and ligand-based approaches as well as its capacity to incorporate desired properties makes it a potentially useful tool for medicinal chemistry The design algorithm has demonstrated its capability to successfully generate molecules with desired properties by incorporating an additional encoding within the input This encoding allows for the translation of various drug discovery-relevant properties with high accuracy into the generated molecules and lipophilicity can be effectively encoded and incorporated into the molecular design process This means that the algorithm can generate molecules that not only possess the desired structural characteristics but also meet specific physical and chemical property requirements The ability to accurately translate these user-defined properties into the generated molecules is a potentially substantial advantage of the approach It enables researchers to identify novel molecules with specific properties and optimize them for desired therapeutic effects the top-ranking computer-generated molecules revealed favorable in vitro ADME properties The results of the study also indicate that ligand-based de novo design outperformed structure-based models for the majority of investigated molecular properties This performance difference could be attributed to the complexity of the input and the availability of training data Whereas a small-molecule graph typically comprises up to 200 edges describing covalent bonds protein binding sites represented by 3D graphs are considerably larger with an average scaling factor of 60 the ligand-based data set used in the study consisted of around 501 k distinct bioaffinity values whereas only about 236 k bioaffinities were accessible to the structure-based training procedure This disparity in training data availability may contribute to the superior performance of the ligand-based design models it is important to acknowledge that one benefit of structure-based design applications is their flexibility in not mandating exceptionally high-quality query ligands for the generation of molecules This applicability can be valuable for in silico library design in scenarios where relevant ligand information is limited or unavailable for newly identified disease-relevant macromolecular targets The comparison between DRAGONFLY models trained on SMILES-strings and SELFIES demonstrated similar overall results in terms of different templates and properties certain trends were observed: Libraries generated using SELFIES exhibited a higher level of diversity and novelty while libraries generated using SMILES-strings achieved higher accuracy in incorporating desired molecular properties such as synthesizability These findings unveil specific strengths and trade-offs associated with de novo design approaches based on SELFIES and SMILES strings Both methodologies have their advantages and limitations and the choice between them depends on specific requirements and available data This latter approach focused on prioritizing novelty and divergence from known ligands allowing for the exploration of new chemical territories These findings highlight the flexibility and versatility of the scoring functions and the ability to customize the weights of different descriptors to achieve specific objectives By balancing the importance of structural similarity we were able to guide the generation of molecules that met the desired criteria for the targeted application These results represent a substantial milestone as they showcase the successful application of a generative deep learning model for molecular de novo design that incorporates ligand activity and selectivity on multiple targets as well as panel selectivity within the same protein class exemplified in the context of nuclear hormone receptors interactome-based deep learning serves as a proof-of-concept for “zero-shot" learning that can be further adapted and customized for specific applications in small molecule drug discovery ultimately leading to more efficient hit-and-lead discovery in bioorganic and medicinal chemistry By leveraging data-driven deep learning and interaction networks this approach offers new avenues for foundation models enabling tailored molecular design strategies and the discovery of innovative drug candidates for 2D graph structures, and Equation (2) Small molecules: The atomic properties of small-molecule ligands were encoded via the following embeddings: 10 atom types [H Proteins: The protein binding site was defined by all protein atoms that are within a 5 Å radius to a ligand atom The atomic properties of the respective protein binding sites were encoded using the following four features: (i) an embedding of the atom types using 22 different embeddings (ii) an embedding of the combination of amino acid and atom types covering 225 different embeddigs (iii) the distance to the closest atom of the bound small-molecule ligand aiming to quantify protein flexibility and intrinsic disorder at the corresponding atom (Section S3) Bond types: Edges were represented by inter-atomic distance in terms of Fourier features, using a sine- and cosine-based encoding for 3D graphs82 Edges were introduced between covalently bound atoms for the 2D graphs and between all atoms within a 4 Å radius from each other for the 3D graphs The selected hyperparameters for the neural network led to a combined count of trainable parameters amounting to 6.94 million (3.49 million for the GTNN encoder and 3.45 million for the LSTM decoder) for the ligand-based design DRAGONFLY model the structure-based design DRAGONFLY model encompassed 7.01 million trainable parameters (3.56 million for the GTNN encoder and 3.45 million for the LSTM decoder) Both structural and scaffold novelty contribute to the overall novelty score, i.e., Equation (12) ranging from 0 (for molecules very close to molecules the training set) to 1.2 (for molecules with no ECFP overlap with the training set and no shared scaffolds) The scatter plot illustrates the relationship between the actual and predicted properties of the molecules The mean absolute errors (MAEs) and Pearson correlation coefficients (r) were calculated to assess the predictive performance of the DRAGONFLY model These statistical measures were derived by comparing the extracted properties of the generated molecules against the properties of the original data set this data extraction process was divided into two stages: In the initial step a compilation of biological targets was obtained compounds were extracted for which specific activities against any of these targets were annotated Single-protein targets that possessed assay information for a minimum of 10 compounds with unique internal identifiers were retrieved from the ChEMBL database A series of activity and annotation filters were then applied to these compounds and any salts and solvents were eliminated For compounds comprising multiple distinct fragments following this “washing" procedure all but the fragment with the highest number of heavy atoms were discarded molecules containing <3 or >100 heavy atoms This procedure yielded a data set of 742 k unique SMILES-strings with annotated biologic affinity Using a cut-off of a binding affinity of 200 nM a maximal SMILES-string length of 97 (using the longest SMILES-length from five randomized sampled SMILES-strings) for the ligand and a minimum number of five ligands per target resulted in a drug-target graph consisting of 501 k unique binding affinities for 360 k unique ligands and 2989 unique target-IDs The PDBbind database (Version 2020) was obtained by downloading it from the link http://www.pdbbind.org.cn/download.php which yielded a collective count of 19,443 protein-ligand structures After filtering out structures annotated with “incomplete ligand structure" “covalent complex," or “incomplete ligand structure" a more refined filtering process was conducted excluding structures with ligand molecular weights outside the range of 100–1200 g mol-1 and binding affinities >10 μM This filtration yielded a collection of 17,824 structures This curated list of entries was then cross-referenced with the target-IDs present within the drug-target graph used for ligand-based design This specific graph contained 501,000 unique binding affinities encompassing around 360,000 unique molecules and 2989 unique target-IDs The outcome of this mapping effort revealed a total of 8351 distinct protein structures associated with 744 unique target-IDs By refining the drug-target graph to exclusively include target-IDs with annotated PDB structures the modified graph encompassed around 263,000 unique binding affinities spanning around 208,000 unique molecules and 744 unique target-IDs The connection between PDB-IDs and target-IDs within ChEMBL was facilitated through UNIPROT-IDs given that both databases provide UNIPROT-IDs for individual proteins the drug-target graph underwent a modification whereby target-IDs encompassing both allosteric and orthosteric ligands were treated as distinct target-IDs HEK293T cells were seeded at the indicated number per well in DMEM-high glucose The cells were incubated overnight at 37 °C Compounds were added to the cells at the indicated concentrations resulting in a final Dimethylsulfoxid (DMSO) concentration of 0.2% The compounds were incubated on the cells for either 16 h or 24 h the medium was carefully removed from the vessel Promega) was prepared according to the manufacturer’s instructions Plates with cells were equilibrated at room temperature for 30 min 25 μl of CTG reagent was added to the cells The plates were then shaken for 2 min and incubated for an additional 15 min at room temperature Luminescence was read afterward with BG Pherastar Compounds 1–3 were characterized in a hybrid reporter gene assay for their agoniztic effect on human nuclear receptors PPARα/γ/δ Compound 1 was tested in an isothermal titration calorimetry (ITC) assay to measure direct binding affinity to the ligand-binding domain of PPARγ ADME properties were measured in standardized assays at Roche 5% glycerol) containing 5% DMSO was titrated with the test compound (1) (100 μM in the same buffer containing 5% DMSO) in 21 injections (1 × 1μl and 20 × 5μl) with an injection interval of 120 s The test compound was titrated into buffer and the buffer was titrated to the PPARγ LBD proteins under otherwise identical conditions The ITC results were analyzed using NanoAnalyze software (TA Instruments Compounds 1–3 were synthesized starting from commercial building blocks. The synthesis and the full analytical characterization of the final compounds and intermediates are described in SI13 A Correction to this paper has been published: https://doi.org/10.1038/s41467-025-55964-1 Computer-based de novo design of drug-like molecules Automated de novo drug design: are we nearly there yet a chemical language and information system Introduction to methodology and encoding rules Automatic chemical design using a data-driven continuous representation of molecules De novo design of bioactive small molecules by artificial intelligence Generative molecular design in low data regimes Leveraging molecular structure and bioactivity with chemical language models for de novo drug design Bidirectional molecule generation with recurrent neural networks Molecular design with long short-term memory networks Chemical language models enable navigation in sparsely populated chemical space Reinvent 2.0: an ai tool for de novo drug design Libinvent: reaction-based generative scaffold decoration for in silico library design Rethinking drug design in the artificial intelligence era Designing molecules with autoencoder networks Integrating qsar modelling and deep learning in drug discovery: the emergence of deep qsar De novo design of nurr1 agonists via fragment-augmented generative deep learning in low-data regime Shape-based generative modeling for de novo drug design Relation: A deep generative model for structure-based de novo drug design Schneuing, A. et al. 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Zenodo https://doi.org/10.5281/zenodo.10671327 (2024) Structural insights into jak2 inhibition by ruxolitinib a potent inhibitor of phospholipidca++ dependent protein kinase Download references Sarah Haller is thanked for technical support Matthias Wittwer and Aynur Ekiciler are greatly acknowledged for generating ADME data Hugentobler is thanked for helpful scientific discussion acknowledges support from the Scholarship Fund of the Swiss Chemical Industry This research was supported by the Swiss National Science Foundation (SNSF Department of Chemistry and Applied Biosciences Roche Pharma Research and Early Development (pRED) writing—review and editing M.Hi.: Methodology M.I.: Methodology—validation of the ranking and scoring procedure J.L.: Methodology—library creation with the RNN baseline model C.C.G.S.: Methodology—validation of the ranking and scoring procedure declare a potential financial and non-financial conflict of interest as co-founders of inSili.com LLC and in their role as scientific consultants to the pharmaceutical industry declare potential financial and non-financial conflict of interest as full employees of F declare potential financial and non-financial conflict of interest as full employees of SARomics Biostructures AB reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41467-024-47613-w Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology Marco Visser is a post-doc researcher at the PThU This research position has been established as a continuation of the endowed chair 'Miskotte/Breukelman for the theological hermeneutics of the biblical root words' by Prof Rinse Reeling Brouwer (2012-2019) and represents the collaboration of the PThU with the De Nieuwe Bijbelschool foundation network of theologians in the tradition of K.H Marco Visser obtained his doctorate for his thesis: 'Pars pro toto Analysis of the figure of the pars pro toto in the work of F.H Breukelman and elaboration based on the texts about the servant of YHWH in Isaiah A Biblical Theological Investigation.' Supervisors of the PhD track were Prof The follow-up research is about the work of Rochus Zuurmond teacher of hermeneutics and professor of Biblical Theology at the UvA from 1981 to 1996 The research question is what the current significance of his way of reading and his vision of the Bible as a whole is for the current field of biblical theology Marco Visser is a pastor in the Goede Herderkerk in Rotterdam-Schiebroek (Protestant Church of the Netherlands) Want to stay informed about PThU news and events Cookies help us improve your experience on our website Functional cookies contribute to a smoothly running website Analytical cookies provide us with insight into how users use the website Marketing cookies allow us to offer you personalised content based on your website visit Some of these cookies are essential, while others help us improve your experience by providing insight into how the site is being used. Read our Cookie and privacy statement for more information Necessary cookies enable basic functionality of this website The website cannot function properly without these cookies and can only be disabled by changing your browser preferences These cookies are used to gather information about your website visit for the purposes of analysing and improving our website These cookies are used to display personalised content to you Discover which of Rotterdam’s vibrant and distinct neighborhoods could be your perfect new home By Shanthy Milne After sustaining catastrophic damage during World War II (WW2) rebuilding itself as one of the Netherlands’ most architecturally innovative and experimental cities The city’s unique design and urban planning are now a major draw for locals and expats alike If you’re also thinking of moving there here’s what you need to know about the city: Looking for somewhere to rent in the Netherlands Spotahome takes the hassle out of househunting by doing the hard work for you and book rental properties all from the comfort of your own home Take the stress out of househunting in the Netherlands with Spotahome Rotterdam is nestled on the Rhine-Meuse-Scheldt Delta (Rijn-Maas-Scheldedelta) in the province of South Holland (Zuid-Holland) in the Netherlands A delta is where rivers join together – in this case the Rhine (Rijn) and Scheldt (Schelde) – and flow onwards – in this instance to the North Sea (Noordzee) Rotterdam is split into two halves by the river Nieuwe Maas (New Meuse). While its city center lies primarily on the northern bank of the river, recent urban development has also spread to the south side of the river, into an area called the Kop van Zuid (Head of South) As with most Dutch cities, traveling by bicycle is the most popular form of transport in Rotterdam. However, if cycling isn’t your thing, rest assured that there is also a reliable and well-connected public transport network including regular bus, tram, metro, and ferry services The train station Rotterdam Centraal (Rotterdam Central Station) is also one of the country’s major transport hubs providing local and international connections to Belgium Roughly 664,000 people live in Rotterdam (2022) making it the second-largest city in the Netherlands They will tell you exactly what they think and won’t mince words (more so than the average Dutch person) They’re also hardworking – the unofficial city slogan is “niet lullen but scrubbing) – and always strive for a bigger and better future This future-forward mentality of its inhabitants is also reflected in Rotterdam’s unique and innovative cityscape. Back in 1940, it took German bombers just fifteen minutes to decimate the city center rather than restoring their city to its former glory the residents of Rotterdam chose to adapt and build a new city that embraced the future you’ll also find numerous modern statement-art statues Rotterdam’s popularity among Dutchies and (international) students means that the housing market is very competitive Whether you’re interested in buying or renting you will need to move fast to secure a property You can find housing in Rotterdam using property websites with customizable search filters Subscribing to property updates on these platforms is a good way to ensure you can respond promptly to suitable listings. Another great way to find a home is by using Living in Rotterdam, Facebook groups Expats searching from abroad will benefit from using a local intermediary. However, even if you are already in the Netherlands, it can be helpful to go through a Dutch real estate agent (makelaar). The Dutch Cooperative Association of Real Estate Agents (Nederlandse Coöperatieve Vereniging van Makelaars – NVM) lists certified agents for international housing in Rotterdam compared to an estimated €25 in Amsterdam and €20 in Utrecht The rental market usually experiences rapid year-on-year changes, with a 13.9% annual increase in the last year That is in comparison with a 17.9% average rise annual rise in Amsterdam and 25.8% in Utrecht Most places are relatively new and energy-efficient it’s better to look toward the outskirts of the city where high-rise buildings give way to more green and spacious areas Rental properties in Rotterdam are usually sublet in one of three states: Prices vary according to the state in which a property is rented Some fully furnished properties are available as short-term rentals which can be ideal for expats while they are searching for a long-term place A typical contract will be for one calendar year Funda, Pararius, and Kamernet are among the most popular websites for browsing up-to-date rental properties in Rotterdam Low-income households can also apply for social housing the waiting list for these properties is incredibly long; in Rotterdam the average waiting time is 52 months (2022) If you’re staying in the Netherlands for five years or more, it might be more economical to purchase a house rather than rent it This is due to tax incentives and long-term benefits attached to Dutch homeownership As with rental properties, the competition to buy a home in Rotterdam is high, and overbidding is common. In 2023, the average sale price of apartments was just over €460,000 and houses were sold for just over €716,000 If those prices haven’t scared you off you can get a mortgage through any bank in the Netherlands There are also mortgage brokers who are experienced in supporting and guiding expats through the buying process Rotterdam is a large city with its outer boundaries reaching the sandy coastline So while the city center is located 30 kilometers inland you can reach the seaside in just 35 minutes by metro Rotterdam itself is divided into 14 districts this overview will be given by district rather than neighborhood Little C Coolhaven a new housing development along the waterfront For more spacious city living (with a matching price tag) expats can look towards the stately buildings around Erasmus Bridge Expats living in Centrum can access premier medical care through the nearby Erasmus Medical Center This center works together with Erasmus University and is a global leader in medical research across numerous disciplines who have several branches in around the city and cosmopolitan atmosphere are a huge draw for locals and expats alike It is also home to a diverse international community making it one of the easiest districts to find and connect with like-minded people offering easy respite from the urban bustle Though there are fewer family-orientated facilities than in some other areas of Rotterdam the lively city center makes up for it with pubs As you might expect, this also leads to more reports of public nuisance than elsewhere in the city and vandalism are also relatively frequent Cycling is the most convenient way to navigate the city and – in typical Dutch style – most Rotterdammers prefer to travel by bike If you aren’t quite ready for life on two wheels the RET (Rotterdamse Elektrische Tram) also provides regular public transport services throughout the city Commuting outside of Rotterdam is also incredibly easy Amsterdam Central Station can be reached within 40 minutes by train and The Hague (Den Haag) is less than half an hour away Owning a car in the Netherlands is costly, and parking is in short supply. Residents who do not have a parking space within their building can apply for a street parking permit (parkeervergunning) and there can be long waiting lists for permits Rotterdam Centrum is the ideal location for expats who enjoy a fast-paced life and the hustle and bustle of a vibrant city Hillegersberg-Schiebroek is known for its nature and expansive green spaces including the lake Bergse Plassen and the river Rotte Housing in this district is more spacious than in the center and particularly suitable for people with children due to its popularity among both local and expat families accommodation within the district can be pricey Hillegersberg is home to the Nord Anglia International School, the only International School located outside of the city center. The school accepts children from ages 3-18. Also within the district is the Dutch Stephanus school offering special classes for non-Dutch speaking children Municipality data shows Hillegersberg-Schiebroek is an incredible place to live in There are no reports of violence or burglaries and levels of public nuisance seem neglectable Residents are also extremely content and don’t have much to complain about it may be the best neighborhood in Rotterdam to take up residence The center of Rotterdam is reachable within roughly 20 minutes by bike Hillegersberg-Schiebroek is idyllic for spacious family living within close proximity to both nature and Rotterdam’s city center In the words of the Rotterdam tourist board, Rotterdam Noord is a working-class district that has been transformed into a design Valhalla Many of the large pre-war properties have been restored making it a highly attractive place to take up residence Rotterdam Noord has a plethora of housing options, from smaller starter apartments and traditionally working-class homes to 1930s houses and modern high-rises. There is also a lively cultural scene, especially in the neighborhood of Het Oude Noorden which offers the perfect blend of hip stores The area closer to Rotterdam Centraal in particular is growing in popularity with entrepreneurs young expats can make the most of the budding social scene that is happening within the repurposed industrial areas Perhaps the most famous place in Rotterdam Noord is the Hofbogen Air Park (Luchtpark Hofbogen) This green city park is situated on the roof of the former train station Hofplein Station and offers visitors a breath-taking view of the city Underneath the arches of the train track, a number of culinary, design, and fashion hotspots are popping up. It is now home to an array of hip businesses, including the jazz bar BIRD and eatery FG Food Labs Also appealing for families is the district’s Rotterdam International Secondary School which offers children the possibility of continuing their education in English while soaking up Dutch culture Despite – or perhaps due to – the upcoming nature of the district, data from the municipality suggests that residents are not super content with their area There are reports of vandalism and public nuisance from traffic and construction and public spaces leave much to be desired Residents also complain about the housing options – more so than elsewhere in Rotterdam – citing small sizes and moderate views as their main frustrations Rotterdam Noord borders the Central Station making it an excellent choice for commuters working outside of the city The city center is accessible within 10-15 by bike Expats looking for comfortable homes within close proximity to the city center will likely fall in love with Rotterdam Noord students and young professionals might be drawn to the district’s hipster scene in and around the main station It’s also an ideal location for expats commuting in and out of Rotterdam The charming and quaint village-like district of Overschie is located just north of Rotterdam Noord and Delfshaven it’s one of the least populated districts of the city there is a wide range of housing options available in Overschie from historic homes to newly built apartments Many of these are more affordable than within districts closer to the city center History buffs will want to check out Museum Overschie where thousands of historical items are on year-round display The district also has local shops and markets; however for more serious shopping it’s best to head towards Rotterdam city center There are development plans for a collective indoor garden but it is unclear when those will be realized Families looking for a local Dutch school can search on the municipality school finder Though less popular with expats than the nearby district of Rotterdam Noord Overschie offers peaceful and spacious living within a reasonable distance of the city center The district has gorgeous nature parks, such as Sidelingepark and Park Zestienhoven. Rotterdammers can find respite from the urban hustle and bustle at Country Estate De Tempel (Buitenplaats de Tempel) a protected estate on the outskirts of Oud-Overschie anyone interested in growing their own crop can join one of the many community gardens in the area Overschie is one of the safest and most socially cohesive districts of Rotterdam It’s far less built up than many of the other neighborhoods favoring green meadow areas and waterways instead Residents – or Overschiënaars as they are called – seem fairly content living in the district though do complain about the lack of facilities and public spaces Rotterdam Central Station remains accessible by bike within 20-30 minutes The A13 highway also runs through the district providing easy road connections for onward travel Overschie is worth a look for more affordable and spacious family living with a village-like feel. Rotterdam The Hague Airport is also located within the district making it an ideal location for those working in aviation or needing to fly to other European destinations frequently As the home of Rotterdam’s two largest universities, it may come as no surprise that Kralingen-Crooswijk is popular among students and young professionals and parks also create a lively atmosphere that will be hard for some people to pass on In terms of housing, the district north of the Nieuwe Maas offers a blend of old and new, with something for all budgets. In Kralingen, the area around Rosenburg Park offers stately villas and avenues of mansion houses cosmopolitan Crooswijk offers more affordable apartments amidst its cozy restaurants and brown bars Nieuw-Crooswijk is also undergoing development and is becoming particularly sought after by young families and couples in search of more affordable homes Located within Kralingen-Crooswijk are Erasmus University Rotterdam (Erasmus Universiteit Rotterdam – EUR) and Rotterdam University of Applied Sciences (RUAS – Hogeschool Rotterdam) the district is well set up to cater to student life hosting four headquarters of the main student associations From December to February, skaters can make the most of being on the ice at the Skating Rink Rotterdam (Schaatsbaan Rotterdam). For year-round indoor swimming, it’s possible to float beneath the glass ceiling of the Eastern Swimming Pool (Oostelijk zwembad) For less sporty leisure time, Kralingen-Crooswijk’s many waterfront bars and eateries offer the perfect escape. One of the most notable restaurants in the area is Restaurant De Tuin which is located in a mansion dating back to 1867 Those requiring medical care can access the best the Netherlands has to offer via the local Erasmus Medical Center This teaching hospital works closely with the university and is a global leader in medical research Located within the district is Kralingse Bos this park offers numerous leisure activities both on and off the water the area becomes a hotspot for BBQing and sunbathing while the petting zoo and playgrounds provide entertainment for younger visitors The district scored well on environmental, social, and safety aspects in the 2022 municipality survey This also reflects its popularity among the residents who have made it their home the public spaces could do with some improvement and there have been reports of public nuisance It’s very easy to bike from Kralingen-Croosijk to Rotterdam city center For those who aren’t comfortable going into traffic on two wheels public transport connections will get you to the center within approximately 15 minutes There is no doubt that Kralingen-Crooswijk is the premier destination for students in Rotterdam it also has a lot to offer young families and professionals who enjoy the buzz of city living with good access to nature and leisure facilities On the north-eastern border of Rotterdam lies Prins Alexander one of the city’s newest residential areas This former agricultural area was developed in 1961 and has several more residential projects underway the district remains very green and has many parks The Alexandrium shopping center is the hub of retail activity in Prins Alexander There are also several entertainment venues and sports facilities to spend the day Families looking for a local Dutch school or daycare can search on the municipality school finder If you’re looking for international options the central districts are not too far away Prins Alexander has several metro stations located within the district as well as a train stop for mainline services You can reach Rotterdam Central Station within nine minutes the same journey takes around 30–45 minutes by bike Since Prins Alexander isn’t one of the most sought-after districts of Rotterdam – especially among families and expats – it is fairly easy to find housing options where you can enjoy quiet and green living Charlois – pronounced Sjaarloos – is one of the oldest areas in Rotterdam, dating back to 1462. The current district is a blend of residential neighborhoods, parks (such as Zuiderpark), and key cultural venues (e.g., Ahoy Rotterdam) It is also one of the most diverse districts in the city so you’ll be sure to mix with an international community If you’re looking to move to Charlois, apartment living is the norm, especially around the built-up central point of Zuiderplein. Further out in the district, you’ll find modern, spacious apartments and even terraced houses (in Pendrecht and De Wielewaal) providing easily accessible 24-hour emergency care The municipality has loads of plans to improve the district. There are many housing developments for both single and family occupancy, and it’s also planning a new seven-acre Nelson Mandela Park on the harborfront That said, the 2022 living situation does not yet reflect this rosy picture. According to data from the Rotterdam municipality residents feel they have a lower quality of life and that their neighborhood is unsafe due to violence that the only actual police reports were regarding nuisance from neighbors Responses also indicated that people don’t like living in (some areas of) Charlois and feel isolated While the environment and green spaces are objectively great residents complain about offensive odors from traffic as well as noise from traffic and construction Charlois connects easily to the city center via bus Resident permits or paid street parking are options in northern Charlois Parking is more readily available further out in the district Charlois is an ideal district for expats looking to mix with an international community it’s also a nice place for anyone wanting to take up residence in close proximity to green open spaces The district of Feijenoord lies on the southern banks of the Nieuwe Maas river and is connected to the city center by the Erasmus bridge it’s ever-evolving with a mix of traditional warehouses and new residential skyscrapers The last one also doubles as a concert venue for large events Younger expats may also be drawn to the now-trendy neighborhood of Katendrecht. This former red-light district area has become a hub for social and cultural activities and is home to many waterfront eateries. For example, The Fenix Food Factory Visitors can enjoy traditionally made cuisine – such as artisanal bread and beers – alongside affordable street food from the market’s revolving food trucks The district’s Ikazia Teaching Hospital offers high-rate 24-hour emergency care many existing residents find themselves priced out of newer developments as wealthier people move in According to data from the municipality Feijenoorders are not very satisfied with their district – especially with the quality of housing Many experience public nuisance from neighbors Feijenoord is connected to the city center by the iconic Erasmus Bridge Residents can easily reach the rest of Rotterdam by bike The city’s Water Taxi is also a reliable and speedy option to get from A to B it often proves to be faster than traveling by road Running like a regular ferry service from the waterfront the Water Taxi also offers private taxi journeys on demand Young expats in particular will find the rapidly developing scene around Feijenoord a big draw It’s an ideal district where you can best experience Rotterdam’s growth and innovation Concert-goers and massive football fans will also enjoy the close proximity to the Kuip Hoogvliet is a former dike village on the southwest outskirts of Rotterdam that is growing in popularity with families making it easy for expats to blend right in While some neighborhoods of Hoogvliet used to be impoverished, the district underwent restructuring in the 2000s. Now, nearly one-fifth of houses are built in the new century. There are also a number of new housing developments underway to broaden the appeal of living around the district’s center including the addition of around 700 new sustainable homes The center of Hoogvliet currently stands as the district’s main shopping area the district is looking to improve and create more green spaces Hoogvliet includes Rotterdam’s green belt (groene gordel) a 10 km long recreational route for cycling The quiet and tranquil nature of living is also reflected in the residents’ quality of life. According to the municipality Hoogvliet is a fine place to take up residence The district has little to no reports of violence dissatisfaction with the number of (public) facilities Responses also indicate that residents are unhappy with their level of social participation and feel left out of society Though further out from Rotterdam’s city center it’s easy to travel to and from Hoogvliet by car or via the district’s metro Going by bike seems out of the question; Rotterdam Centrum is approximately an hour away Hoogvliet is perfect for families who want to live close to nature it has great potential for anyone looking to live in an up-and-coming district for cheap On the southeast side of Rotterdam, lies the vibrant and diverse district of IJsselmonde locals and expats can experience a mix of urban living and green spaces The original dike village of Oud-IJsselmonde which is close to the Nieuwe Maas waterfront is the most picturesque part of the district where you can find authentic Dutch row houses and charming streets Typically one of Rotterdam’s quieter districts, the highlight of IJsselmonde’s social calendar from 1700 through to 2020, was its annual 2-day horse market and its accompanying fair, art exhibition, and concert. However, it has since been decided to discontinue the centuries-old event Expats with children will delight in going to The Play Factory (De Speelfabriek) a play workshop for children from 5 to 12 years old where they can explore making IJsselmonde boasts a scenic waterfront area where locals often go sailing. It’s also home to the large nature park Park De Twee Heuvels which includes a skate park and indoor pool Nestled between Rotterdam and Dordrecht is a gorgeous recreational area where you can enjoy the typical polder nature scene – complete with green dikes Data from the Rotterdam municipality suggests that IJsselmonde has great social initiatives (e.g. and residents don’t seem all that content to live there You can travel between the center of IJsselmonde and Rotterdam Centraal by bike or public transport quieter environment that’s still within close proximity of Rotterdam will benefit from the low-cost housing options in IJsselmonde the harbor town of Delfshaven was built to provide the city of Delft waterway access to the Nieuwe Maas river The district was spared wartime destruction and now stands proud as Rotterdam’s most historic area and traditional Dutch architecture offer up a picture-postcard area to live in Rental prices range from €900-2,500 for apartments and €1,500-4,500 for houses Purchase prices can differ greatly; prices range from €250,000-400,000 for apartments and €400,00-1,300,000 for houses which produces and serves local beers such as Pilgrim beer (pilgrim bier) the number of facilities and schools is more limited than elsewhere in Rotterdam expat parents can register their offspring with these district schools that offer special provisions for children with little to no Dutch language skills: Delfshaven was known for its herring fishers and gin distilleries The latter tradition is still apparent in the many waterside gin bars Many of the area’s historic townhouses are now home to quaint antique shops According to municipality data Delfshaven is a nice neighborhood that is safe from theft residents feel there is more present than they report Some people also indicate feeling discriminated against in and around their neighborhood Delfshaven is just a 13-minute bike ride away from Rotterdam Central Station There are also regular bus and tram services that connect to the city center Delfshaven is perfect for expats wishing to enjoy quieter neighborhood living Hoek van Holland is Rotterdam’s only coastal district It is located some 30 km outside of the city center and Hoek van Holland is an idyllic place to escape city life and many beach clubs are a siren call for anyone looking to go on a day trip or short getaway But the district also has a number of attractive homes for those who want to enjoy beachside living more permanently Most Hoekenezen – as the area’s residents are known – reside in the main village There are also a number of housing developments underway for newcomers to take up residence and sports facilities including a tennis court and swimming pool there is also a lighthouse (vuurtoren) that currently serves as a museum Hoek van Holland’s sandy beaches are a hotspot among locals and tourists alike, and with good reason. They have repeatedly received the iconic Blue Flag award meaning they meet the highest level of environmental and safety standards The tumultuous history of the area is drawn into the landscape as well Traces of the German Nazi defense line that stretched along the coast from Norway to Spain are still evident in the sand dunes Various wartime bunkers and underground tunnels offer insight into the history amidst the protected areas of flora and fauna Data shows this district of Rotterdam is a great place to live in Hoek van Holland has no reports of public nuisance Responses from residents also show that they’re mostly content they complain about the lack of public facilities Hoek van Holland has its own metro station which opens straight onto the beachfront The journey to or from Rotterdam Central Station takes about 35 minutes The district also serves as a port for the ferry service Stenaline from which you can set sail for Harwich in the UK on a daily basis Hoek van Holland is great for beach-loving expats who want to live near Rotterdam and don’t mind the small village life Pernis is a garden village in the middle of the port area of ​​Rotterdam It is located on the west side of the city and is home to one of the largest oil refineries in the Netherlands While that might scare some newcomers away others will be enchanted by the district’s laid-back character As Pernis is mostly an industrial and residential district there aren’t many facilities to keep bored locals and expats entertained and excellent transport connections to the city center where you’ll likely find more things to do residents have a panoramic view of the water with its many ships the district offers a clear and extraordinary view of the starry sky every night Nature parks Deijffelbroek Park and Pernisser Park are a favorite among locals for walking The latter also has an outdoor swimming pool and a Children’s Forest where city folk can get acquainted with different types of trees The district seems to be a bit of a hidden secret. Pernis is extremely safe and socially cohesive It also seems to be one of the only districts of Rotterdam where residents don’t report public nuisance While there are objectively few facilities inhabitants seem very content with their living situation Pernis is connected to the Rotterdam city center by bus and metro services. The metro also runs through the Benelux Tunnel an ingenious river crossing underneath the Nieuwe Maas This tunnel also allows vehicles and bikes to access routes to Schiedam and Vlaardingen.  From the waterfront, the Water Taxi is also a great option to travel to the heart of Rotterdam in no time Expats with a love for water will enjoy the affordable housing options and incredible views that Pernis has to offer West of the city center is Rozenburg an island district that is connected to the mainland by bridges and tunnels The district is located between Rotterdam Port and the more industrial areas of the city Rozenburg has a distinct suburbian-like feel with just one main residential area Expats will find spacious middle-class housing options with quite a bit of greenery there aren’t many facilities to keep bored residents occupied during their days off and a shopping street with local shops and eateries Expats with children will also enjoy visiting the local windmill and petting zoo Located towards the shoreline is Rozenburg Headland (Landtong) a 10 km long nature reserve where visitors can experience the rugged nature that makes this part of the Netherlands so beautiful you’ll find flocks of migratory birds Residents of Rozenburg are very socially active and organize loads of activities, including markets, music festivals, and cycling and walking tours. Municipality data shows the district is a great place to live without the fear of crime Responses suggest that people are mostly content despite the lack of public facilities The district of Rozenburg is quite far from Rotterdam Centrum and it’ll take residents about an hour by tram or train to reach the city Those who prefer to go by bike can expect around an hour and a half of travel time Rozenburg is an ideal district for expats looking for a quieter suburban community life close by the shoreline On the whole, Rotterdam is considered one of the more criminally dangerous cities in the Netherlands, due to reports of explosions In 2022, it was the city with the most homicides (16 victims in Rotterdam, compared to a total of 142 in the Netherlands). Rotterdam also had just over 11,000 reports of violent and sexual crimes (the Netherlands totaled nearly 80,100 cases in 2022) The most registered crimes in 2022 occurred in the districts of: expats should exercise common sense to protect their personal safety and their belongings when traveling alone at night or in busy areas of Rotterdam where pickpocketing might occur With regard to air quality and pollution The Dutch government and local authorities have implemented strict regulations to mitigate the impact of the city’s industries on air quality and the local environment you may wish to avoid setting up homes in certain areas near ports and highways There are also a number of recruitment agencies dedicated to pairing internationals with companies in Rotterdam and the surrounding areas Shanthy is a writer and documentary producer with ten years of experience making films for the BBC and Channel 4 Born in London to Sri Lankan/Malaysian parents She also writes fiction and was a finalist on Penguin’s Write Now scheme You can claim different types of child benefits in the Netherlands Although Amsterdam is typically the number one hub for expats there are plenty of other cities in the Netherlands worth your while We explain the complex secondary school system in the Netherlands including the three public streams and various international options ligt gebied Hillegersberg-Schiebroek (HIS) De gemeente pleegt groot onderhoud aan het Argonautenpark en het Molenpark Er is veel aandacht voor de verbetering van de natuur en de opvang van water Het onderhoud aan de parken start naar verwachting in augustus of september We bevorderen de biodiversiteit van de parken door gevarieerde beplanting die niet alleen uit bomen en gras bestaat maar ook uit kruiden en struiken Er komt een meer geleidelijke overgang tussen water en land zodat er meer planten en dieren in het water kunnen leven terwijl die onmisbaar is voor het bestuiven van planten Een bijenlandschap is een fijne plek voor bijen om te nestelen We verleggen verschillende paden en hogen ze op die ondergronds het water van de ene naar de andere sloot voeren In het Argonautenpark vervangen we één duiker Er komt een opvang voor water in de bosplantsoenen In het Argonautenpark maken we ook een tijdelijke waterberging (een wadi) op het grote veld In juni 2024 werd het vrij liggende fietspad langs de Berberisweg opgeheven bleek dat veel buurtbewoners het daar niet mee eens waren Dit had er onder andere mee te maken dat niet de juiste juridische procedure was gevolgd bij het weghalen van het fietspad Inmiddels is de juiste procedure doorlopen en hebben omwonenden alsnog kans gehad om hun bezwaren kenbaar te maken aan de Algemene Bezwaarschriftencommissie (ABC) De Commissie heeft na een complete overweging van het besluit geadviseerd om het fietspad weer terug aan te leggen De gemeente heeft besloten om dit advies over te nemen en het fietspad weer aan te leggen op de plek waar het voorheen lag Het milieupark Hillegersberg-Schiebroek is gesloten Inwoners kunnen hier hun afval en grofvuil en gratis inleveren Het milieupark heeft ook aparte containers voor tweedehandsspullen die hergebruikt kunnen worden Zo gaan oude nog bruikbare spullen naar kringloopwinkel 'Het Goed' Kijk voor meer informatie op pagina Milieupark Sinds juli 2024 is er een tijdelijk parkeerterrein op de Abeelweg in Schiebroek in het grasveld naast basisschool Tuinstad Dit tijdelijke parkeerterrein moet de (parkeer)overlast van de bezoekers van Plaswijckpark in de wijk te verminderen Het terrein is alleen bedoeld voor bezoekers van Plaswijckpark Parkeren kan alleen op piekmomenten in de vakantieperiode Op andere momenten is het parkeerterrein afgesloten  Het parkeerterrein blijft er maximaal 2 jaar liggen.Met Plaswijckpark en de school zijn afspraken gemaakt over het gebruik Met speciale tijdelijke verf geven we een looproute op de stoep aan De looproute loopt zo min mogelijk door de woonwijk om overlast te voorkomen Om het gebruik van openbaar vervoer te stimuleren krijgt de looproute door de Meidoornweide richting de tram extra nadruk Heeft u vragen? Mail dan naar: maatregelenplaswijckparkSO@rotterdam.nl. Link opent een externe pagina In de zomer van 2024 hield vroeg de gemeente waar honden los mochten in drie parken van Hillegersberg-Schiebroek Ook over de uitlaatzone op de Wilgenlei konden bewoners meedenken De enquête over losloopzones in het Schiebroeksepark Melanchtonpark en Prinsenmolenpark is door 1.633 mensen ingevuld De meeste mensen willen dat het losloopgebied in het Prinsenmolenpark groter wordt maar zonder de oever van de Rotte en het fietspad In het Schiebroeksepark willen de respondenten de huidige losloopzone behouden en uitbreiden met een ronde om de sportvelden en een nieuw hondenstrand Tot de oplevering (medio 2026) van het nieuwe hondenstrand blijft het oude hondenstrand bestaan In het Melanchtonpark wil men de huidige losloopzone behouden Alleen aan de kant van de Torteltuin vindt een kleine correctie van de grens van de losloopzone plaats Melanchtonpark en Prinsenmolenpark is door 1.633 mensen ingevuld.De meeste mensen willen dat het losloopgebied in het Prinsenmolenpark groter wordt Uitlaatzone WilgenleiDe enquête over de huidige uitlaatzone op de Wilgenlei Meer dan de helft van de respondenten (57,5%) vond de optie honden aanlijnen en poep opruimen door hondeneigenaren het beste voor deze plek Dat geldt voor beide kanten van de Wilgenlei In de huidige situatie is hondenpoep opruimen niet verplicht Hoe verder?We passen het aanwijsbesluit voor de losloopzones in de 3 parken en de uitlaatzone van de Wilgenlei aan. Dit besluit wordt genomen door het college van B&W. U kunt zich laten informeren via  www.officielebekendmakingen.nl. Link opent een externe pagina Daarna geldt een bezwaartermijn van 6 weken na publicatie Op basis van de bezwaarprocedure wordt het besluit definitief of Daarna wijzigen we de borden in de parken en op de Wilgenlei In Schiebroek vervangt de gemeente veel rioolbuizen.We zetten ze op een rijtje Three explosions likely caused by firework bombs occurred in different locations in Rotterdam early Friday morning There was a great deal of damage caused at each location The first blast happened at a café on the Kreekplein in Rotterdam-Zuid at about 1:25 a.m To extinguish the fire that started after the explosion the fire brigade had to demolish part of the ceiling there was also a blast at an apartment building on Forelstraat in the Hoogvliet neighborhood Some exterior doors for the ground floor apartments were damaged and a number of homes had to be temporarily evacuated The third incident took place at about 3 a.m off De Blecourtstraat in the Schiebroek district residents were asked to leave the area as a few homes were evacuated after the explosion occurred on an apartment porch On Wednesday, another explosion occurred in a café located a few kilometers from the Kreekplein incident It was also likely caused by a firework bomb Both cafes are known as places frequently visited by supporters of Rotterdam football club Feyenoord It is still being investigated whether the incidents are connected to the Feyenoord-Ajax game that will be played on Sunday Police could not yet establish the connection between the incidents