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Chemical Space as a Source for New Drugs

English title Chemical Space as a Source for New Drugs
Applicant Reymond Jean-Louis
Number 146363
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.05.2013 - 30.04.2016
Approved amount 184'650.00
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Keywords (6)

Chemical space; Virtual screening; acetyl choline receptors; computer-aided drug design; databases; cheminformatics

Lay Summary (French)

Lead
En chimie médicinale, on parle d'"espace chimique" pour décrire l'ensemble de toutes les petites molécules ayant un intérêt potentiel comme médicament. Cet ensemble comprend des millions de molécules déjà connues, ainsi qu'un nombre encore beaucoup plus grand de molécules encore inconnues.Explorer cet immense espace chimique devrait permettre de découvrir un grand nombre de nouvelles substances actives, et ainsi faciliter le développement de nouveaux médicaments.
Lay summary

Notre projet s'intéresse à énumérer systématiquement toutes les molécules encore inconnues sous forme d'une banque de données nommée "GDB" (Generated DataBase), et à utiliser cette banque de données pour découvrir de nouvelles substances bioactives. Nous avons déjà réalisé cette énumération jusqu'à des molécules de 17 atomes, et allons étendre cette énumeration pour couvrir l'entier de l'espace chimique d'intérêt pharmaceutique, à savoir jusqu'à des molécules de 34 atomes. Cette banque de donnée comprendra probablement plus de mille milliard de molécules, ouvrant des horizons nouveaux et insoupçonnés sur le potentiel d'innovation de la chimie organique.

La médecine moderne dépend de l'invention continue de nouvelles substances bioactives, en particulier pour faire face au défis des nouvelles maladies et des phénomènes de résistance qui rendent beaucoup de médicament inactifs. Il devient de plus en plus difficile de découvrir des nouvelles molécules par des approches classiques. Notre stratégie d'exploration de l'espace chimique devrait permettre de débloquer les limites actuelles et de faciliter l'élaboration d'un grand nombre de médicaments innovants. 

Direct link to Lay Summary Last update: 27.03.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Fragment-based Drug Discovery
Reymond Jean-Louis, Visini Ricardo, Awale Mahendra, Erlanson Ed. D.A., Jahnke W. (2016), Fragment-based Drug Discovery, in Carmot Therapeutics (ed.), Wiley-VCH, Weinheim, 57-75.
PDB-Explorer: a Web-Based Interactive Map of the Protein Data Bank in Shape Space
Jin Xian, Awale Mahendra, Zasso M., Kostro D., Patiny L., Reymond Jean-Louis (2016), PDB-Explorer: a Web-Based Interactive Map of the Protein Data Bank in Shape Space, in BMC Bioinformatics, 2015(16), 339.
Similarity Mapplet: Interactive Visualization of the Directory of Useful Decoys and ChEMBL in High Dimensional Chemical Spaces
Awale Mahendra, Reymond Jean-Louis (2015), Similarity Mapplet: Interactive Visualization of the Directory of Useful Decoys and ChEMBL in High Dimensional Chemical Spaces, in Journal of Chemical Information and Modeling, 55(8), 1509-1516.
Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints
Awale Mahendra, Jin Xian, Reymond Jean-Louis (2015), Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints, in Journal of Cheminformatics, 7(3), 1-15.
The Chemical Space Project
Reymond Jean-Louis (2015), The Chemical Space Project, in Accouts of Chemical Research, 48(3), 722-730.
“Social” Network of Isomers Based on Bond Count Distance: Algorithms
Kouri Tina M., Awale Mahendra, Slyby James K., Reymond Jean-Louis, Mehta Dinesh P. (2014), “Social” Network of Isomers Based on Bond Count Distance: Algorithms, in Journal of Chemical Information and Modeling, 54(1), 57-68.
A multi-fingerprint browser for the ZINC database
Awale Mahendra, Reymond Jean-Louis (2014), A multi-fingerprint browser for the ZINC database, in Nucleic Acids Research, 1-5.
Atom Pair 2D-Fingerprints Perceive 3D-Molecular Shape and Pharmacophores for Very Fast Virtual Screening of ZINC and GDB-17
Awale Mahendra, Reymond Jean-Louis (2014), Atom Pair 2D-Fingerprints Perceive 3D-Molecular Shape and Pharmacophores for Very Fast Virtual Screening of ZINC and GDB-17, in Journal of Chemical Information and Modeling, 54(7), 1892-1907.
Considerations on the Drug-Like Chemical Space
Reymond Jean-Louis, Ruddigkeit Lars, Awale Mahendra, Jacoby Ed. E. (2014), Considerations on the Drug-Like Chemical Space, in Jacoby E. (ed.), Pan Standford Publishing, Singapore, 39-64.
Discovery of Potent Positive Allosteric Modulators of the α3β2 Nicotinic Acetylcholine Receptor by a Chemical Space Walk in ChEMBL
Bürgi Justus, Awale Mahendra, Boss Silvan D., Schaer Tifany, Marger Fabrice, Viveros-Paredes Juan M., Bertrand Sonia, Gertsch Jürg, Bertrand Daniel, Reymond Jean-Louis (2014), Discovery of Potent Positive Allosteric Modulators of the α3β2 Nicotinic Acetylcholine Receptor by a Chemical Space Walk in ChEMBL, in ACS Chemical Neuroscience, 5(5), 346-359.
Expanding the fragrance chemical space for virtual screening
Ruddigkeit Lars, Awale Mahendra, Reymond Jean-Louis (2014), Expanding the fragrance chemical space for virtual screening, in Journal of Cheminformatics, 6(27), 1-12.
The Chemical Space of Flavours
Ruddigkeit Lars, Reymond Jean-Louis, Martinez-Mayorga Ed. K., Medina-Franco J.L. (2014), The Chemical Space of Flavours, in Martinez-Mayorga Ed. K. (ed.), 83-96.
Article Previous Article Next Article Table of Contents SMIfp (SMILES fingerprint) Chemical Space for Virtual Screening and Visualization of Large Databases of Organic Molecules
Schwartz Julian, Awale Mahendra, Reymond Jean-Louis (2013), Article Previous Article Next Article Table of Contents SMIfp (SMILES fingerprint) Chemical Space for Virtual Screening and Visualization of Large Databases of Organic Molecules, in Journal of Chemical Information and Modeling, 53(8), 1979-1989.
MQN-Mapplet: Visualization of Chemical Space with Interactive Maps of DrugBank, ChEMBL, PubChem, GDB-11, and GDB-13
Awale Mahendra, van Deursen Ruud, Reymond Jean-Louis (2013), MQN-Mapplet: Visualization of Chemical Space with Interactive Maps of DrugBank, ChEMBL, PubChem, GDB-11, and GDB-13, in Journal of Chemical Information and Modeling, 53(2), 509-518.
Visualization and Virtual Screening of the Chemical Universe Database GDB-17
Ruddigkeit Lars, Blum Lorenz C., Reymond Jean-Louis (2013), Visualization and Virtual Screening of the Chemical Universe Database GDB-17, in Journal of Chemical Information and Modeling, 53(1), 56-65.

Collaboration

Group / person Country
Types of collaboration
Prof. D. Bertrand/HiQScreen Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
GLISTEN COST Meeting on GPCR Talk given at a conference Chemical Space for Drug Discovery 07.04.2016 Erlangen, Germany Reymond Jean-Louis;
ACS Meeting San Diego, MPPG 106 Talk given at a conference Mining the Chemical Universe Database GDB-17 for Drug Discovery 17.03.2016 San Diego, United States of America Reymond Jean-Louis;
Seminar at Dart Neuroscience, San Diego, USA Individual talk Exploiting Chemical Space for Drugs and Fragments 15.03.2016 San Diego, United States of America Reymond Jean-Louis;
Seminar at the University of Tianjin, China Individual talk Chemical Space for Drug Discovery 22.10.2015 Tianjin, China Reymond Jean-Louis;
Seminar at the University of Nankai, China Individual talk Chemical Space Exploration of Bioactive Peptides 21.10.2015 Nankai, China Reymond Jean-Louis;
11th Global Conference Compound Libraries Talk given at a conference The Chemical Space Project 13.10.2015 Berlin, Germany Reymond Jean-Louis;
7ème journées de la société française de chimioinformatique Talk given at a conference Chemical Space for Drug Discovery 08.10.2015 Nizza, France Reymond Jean-Louis;
Chemical Ontology Workshop, Novartis, Basel Talk given at a conference How to Find New Drugs in Chemical Space 02.10.2015 Basel, Switzerland Reymond Jean-Louis;
Seminar at the Biozentrum, Basel Individual talk How to Find New Drugs in Chemical Space 28.09.2015 Basel, Switzerland Reymond Jean-Louis;
Seminar at the Université de Toulouse, France Individual talk Chemical Space Exploration of Bioactive Peptides 18.09.2015 Toulouse, France Reymond Jean-Louis;
Assembly of a diverse 10M GDB fragment set Poster Fall Meeting SCG 04.09.2015 Lausanne, Switzerland Visini Ricardo;
Gordon Computer Aided Drug Design Poster Assembly of a diverse 10M GDB fragment set 19.07.2015 Mount Snow, VT, United States of America Visini Ricardo;
Seminar at the Université de Mulhouse, France Individual talk Drug Discovery in Chemical Space 04.06.2015 Mulhouse, France Reymond Jean-Louis;
Glisten Allschwil Poster Assembly of a diverse 10M GDB fragment set 01.04.2015 Allschwil, Switzerland Visini Ricardo;


Associated projects

Number Title Start Funding scheme
130001 The GDB approach to drug discovery 01.05.2010 Project funding (Div. I-III)
125762 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase I) 01.11.2010 National Centres of Competence in Research (NCCRs)
119987 Exploring the chemical universe for drug discovery 01.05.2008 Project funding (Div. I-III)
165997 Exploiting and Extending GDB for Drug Discovery 01.05.2016 Project funding (Div. I-III)
130001 The GDB approach to drug discovery 01.05.2010 Project funding (Div. I-III)
125781 NCCR Chemical Biology: Visualisation and Control of Biological Processes Using Chemistry (phase I) 01.12.2010 National Centres of Competence in Research (NCCRs)

Abstract

The continuous discovery of new small molecule drugs is essential to the success of modern medicine, in particular to address unmet medical needs, to combat emerging infectious diseases, and to improve existing therapies. Recently, it has become increasingly difficult to develop such new drugs, largely due to lack of efficacy, side effects and toxicity issues. These difficulties have raised the attention to the problem of carefully designing drugs taking multiple parameters into accounts, and have spurred the development of computer-aided drug design as key discipline to support drug discovery. Part of these efforts are devoted to de novo drug design, an approach which aims to select molecules by virtual screening (VS) to focus efforts on the most promising compounds and increase productivity. We have contributed to this field by enumerating the Chemical Universe Databases, which list all organic molecules that are possible following simple rules of chemical stability and synthetic feasibility, and represent an extremely vast reservoir of potential new drugs. In this proposal, we will expand our exploration of chemical space in search for new drugs in three projects addressing enumeration and VS methodology and their application in drug discovery.
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