A bottom-up approach to find lead compounds in expansive chemical spaces
Abstract Drug discovery starts with the identification of a “hit” compound that, following a long and expensive optimization process, evolves into a drug candidate. Bigger screening collections increase the odds of finding more and better hits. For this reason, large pharmaceutical companies have in...
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Nature Portfolio
2025-08-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01610-2 |
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| author | Álvaro Serrano-Morrás Andrea Bertran-Mostazo Marina Miñarro-Lleonar Arnau Comajuncosa-Creus Adrià Cabello Carme Labranya Carmen Escudero Tian V. Tian Inna Khutorianska Dmytro S. Radchenko Yurii S. Moroz Lucas Defelipe David Ruiz-Carrillo Maria Garcia-Alai Robert Schmidt Matthias Rarey Patrick Aloy Carles Galdeano Jordi Juárez-Jiménez Xavier Barril |
| author_facet | Álvaro Serrano-Morrás Andrea Bertran-Mostazo Marina Miñarro-Lleonar Arnau Comajuncosa-Creus Adrià Cabello Carme Labranya Carmen Escudero Tian V. Tian Inna Khutorianska Dmytro S. Radchenko Yurii S. Moroz Lucas Defelipe David Ruiz-Carrillo Maria Garcia-Alai Robert Schmidt Matthias Rarey Patrick Aloy Carles Galdeano Jordi Juárez-Jiménez Xavier Barril |
| author_sort | Álvaro Serrano-Morrás |
| collection | DOAJ |
| description | Abstract Drug discovery starts with the identification of a “hit” compound that, following a long and expensive optimization process, evolves into a drug candidate. Bigger screening collections increase the odds of finding more and better hits. For this reason, large pharmaceutical companies have invested heavily in high-throughput screening (HTS) collections that can contain several million compounds. However, this figure pales in comparison with the emergent on-demand chemical collections, which have recently reached the trillion scale. These chemical collections are potentially transformative for drug discovery, as they could deliver many diverse and high-quality hits, even reaching lead-like starting points. But first, it will be necessary to develop computational tools capable of efficiently navigating such massive virtual collections. To address this challenge, we have conceived an innovative strategy that explores the chemical universe from the bottom up, performing a systematic search on the fragment space (exploration phase), to then mine the most promising areas of on-demand collections (exploitation phase). Using a hierarchy of increasingly sophisticated computational methods to remove false positives, we maximize the success probability and minimize the overall computational cost. A basic implementation of the concept has enabled us to validate the strategy prospectively, allowing the identification of new BRD4 (BD1) binders with potencies comparable to stablished drug candidates. |
| format | Article |
| id | doaj-art-1f4fa385d19746d1925360b072e86c61 |
| institution | DOAJ |
| issn | 2399-3669 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-1f4fa385d19746d1925360b072e86c612025-08-20T03:04:26ZengNature PortfolioCommunications Chemistry2399-36692025-08-018111110.1038/s42004-025-01610-2A bottom-up approach to find lead compounds in expansive chemical spacesÁlvaro Serrano-Morrás0Andrea Bertran-Mostazo1Marina Miñarro-Lleonar2Arnau Comajuncosa-Creus3Adrià Cabello4Carme Labranya5Carmen Escudero6Tian V. Tian7Inna Khutorianska8Dmytro S. Radchenko9Yurii S. Moroz10Lucas Defelipe11David Ruiz-Carrillo12Maria Garcia-Alai13Robert Schmidt14Matthias Rarey15Patrick Aloy16Carles Galdeano17Jordi Juárez-Jiménez18Xavier Barril19Unitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Unitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Unitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Institut de Recerca Biomèdica (IRB Barcelona) and Barcelona Institute of Science and Technology (BIST). c/ Baldiri i ReixacUnitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Unitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Upper Gastrointestinal and Endocrine Tumor Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusUpper Gastrointestinal and Endocrine Tumor Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital CampusEnamine Ltd.Enamine Ltd.Enamine Ltd.European Molecular Biology LaboratoryEuropean Molecular Biology LaboratoryEuropean Molecular Biology LaboratoryCenter for Bioinformatics, University of Hamburg ZBHCenter for Bioinformatics, University of Hamburg ZBHInstitut de Recerca Biomèdica (IRB Barcelona) and Barcelona Institute of Science and Technology (BIST). c/ Baldiri i ReixacUnitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Unitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Unitat de Fisicoquímica, Departament de Farmàcia i Tecnologia Farmacéutica, i Fisicoquímica. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona (UB)Abstract Drug discovery starts with the identification of a “hit” compound that, following a long and expensive optimization process, evolves into a drug candidate. Bigger screening collections increase the odds of finding more and better hits. For this reason, large pharmaceutical companies have invested heavily in high-throughput screening (HTS) collections that can contain several million compounds. However, this figure pales in comparison with the emergent on-demand chemical collections, which have recently reached the trillion scale. These chemical collections are potentially transformative for drug discovery, as they could deliver many diverse and high-quality hits, even reaching lead-like starting points. But first, it will be necessary to develop computational tools capable of efficiently navigating such massive virtual collections. To address this challenge, we have conceived an innovative strategy that explores the chemical universe from the bottom up, performing a systematic search on the fragment space (exploration phase), to then mine the most promising areas of on-demand collections (exploitation phase). Using a hierarchy of increasingly sophisticated computational methods to remove false positives, we maximize the success probability and minimize the overall computational cost. A basic implementation of the concept has enabled us to validate the strategy prospectively, allowing the identification of new BRD4 (BD1) binders with potencies comparable to stablished drug candidates.https://doi.org/10.1038/s42004-025-01610-2 |
| spellingShingle | Álvaro Serrano-Morrás Andrea Bertran-Mostazo Marina Miñarro-Lleonar Arnau Comajuncosa-Creus Adrià Cabello Carme Labranya Carmen Escudero Tian V. Tian Inna Khutorianska Dmytro S. Radchenko Yurii S. Moroz Lucas Defelipe David Ruiz-Carrillo Maria Garcia-Alai Robert Schmidt Matthias Rarey Patrick Aloy Carles Galdeano Jordi Juárez-Jiménez Xavier Barril A bottom-up approach to find lead compounds in expansive chemical spaces Communications Chemistry |
| title | A bottom-up approach to find lead compounds in expansive chemical spaces |
| title_full | A bottom-up approach to find lead compounds in expansive chemical spaces |
| title_fullStr | A bottom-up approach to find lead compounds in expansive chemical spaces |
| title_full_unstemmed | A bottom-up approach to find lead compounds in expansive chemical spaces |
| title_short | A bottom-up approach to find lead compounds in expansive chemical spaces |
| title_sort | bottom up approach to find lead compounds in expansive chemical spaces |
| url | https://doi.org/10.1038/s42004-025-01610-2 |
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