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The GDB approach to drug discovery

English title The GDB approach to drug discovery
Applicant Reymond Jean-Louis
Number 130001
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie, Biochemie und Pharmazie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.05.2010 - 30.04.2013
Approved amount 258'365.00
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Keywords (6)

chemical space; cheminformatics; databases; drug discovery; virtual screening; nicotinic receptor

Lay Summary (English)

Lead
Lay summary

Drug discovery is vital to modern medicine. In recent years drug discovery has been seriously hampered by the apparent lack of innovative chemical structures, which are key to the ability to develop new chemical entities. To address this problem, we have carried out an exhaustive enumeration of chemical space for small fragments, and made available the chemical space up to 13 non-hydogen atoms in the form of the database GDB-13, which with 977 million is the largest public databases of structure available today. There has been over 3000 downloads of the database, including from the best cheminformatics laboratories world-wide.Our current research aims at extending GDB, as well as at searching for new small molecule drugs in GDB. The drug discovery part uses virtual screening to identify "virtual hits", i.e. small molecules showing high activity scores in silico. This report summarizes the key advances for the period 3.2011-3.2012.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
“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, 2014(54), 57-68.
Expanding the Topological Space of Bioactive Peptides
Reymond Jean-Louis, Darbre Tamis (2013), Expanding the Topological Space of Bioactive Peptides, in CHIMIA, 67(12), 864-867.
SMIfp (SMILES fingerprint) Chemical Space for Virtual Screening and Visualization of Large Databases of Organic Molecules
Schwartz Julian, Awale Mahendra, Reymond Jean-Louis (2013), SMIfp (SMILES fingerprint) Chemical Space for Virtual Screening and Visualization of Large Databases of Organic Molecules, in Journal of Chemical Information and Modeling, 2013(53), 1979-1989.
Cluster analysis of the DrugBank chemical space using molecular quantum numbers
Awale Mahendra, Reymond Jean-Louis (2012), Cluster analysis of the DrugBank chemical space using molecular quantum numbers, in Bioorganic & Medicinal Chemistry, online only, not known yet(online onl), not known-not known.
Exploring chemical space for drug discovery using the chemical universe database
Awale Mahendra, Reymond Jean-Louis (2012), Exploring chemical space for drug discovery using the chemical universe database, in ACS Chem. Neurosci, online only, not known yet(online onl), online onl-online onl.
The enumeration of chemical space
Reymond Jean-Louis, Ruddigkeit Lars, Blum Lorenz, van Deursen Ruud (2012), The enumeration of chemical space, in WIREs Comput. Mol. Sci, online only, not known yet(online onl), online onl-online onl.
Discovery of a7-Nicotinic Receptor Ligands by Virtual Screening of the Chemical Universe Database GDB-13
Blum Lorenz, van Deursen Ruud, Bertrand Sonia, Mayer Milena, Bürgi Justus, Bertrand Daniel, Reymond Jean-Louis (2011), Discovery of a7-Nicotinic Receptor Ligands by Virtual Screening of the Chemical Universe Database GDB-13, in J. Chem. Inf. Model, 51(12), 3105-3112.
Exploring the chemical space of known and unknown organic small molecules at www.gdb.unibe.ch
Blum Lorenz, van Deursen Ruud, Reymond Jean-Louis (2011), Exploring the chemical space of known and unknown organic small molecules at www.gdb.unibe.ch, in Chimia, 65(11), 863-867.
Visualisation and subsets of the chemical universe database GDB-13 for virtual screening
Blum Lorenz, van Deursen Ruud, Reymond Jean-Louis (2011), Visualisation and subsets of the chemical universe database GDB-13 for virtual screening, in Comput. Aided Mol. Des., 25(7), 637-647.
Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem
von Deursen Ruud, Blum Lorenz, Reymond Jean-Louis (2011), Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem, in Comput. Aided Mol. Des., 25(7), 649-662.
What we have learned from crystal structures of proteins to receptor function
Reymond Jean-Louis, van Deursen Ruud, Bertrand Daniel (2011), What we have learned from crystal structures of proteins to receptor function, in Biochem. Pharmacol., 82(11), 1521-1527.
Synthesis and Nicotinic Receptor Activity of Chemical Space Analogs of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) and 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo...
Bréthous Lise, Garcia-Delgado N., Schartz Julian, Bertrand Sonia, Bertrand Daniel, Reymond Jean-Louis, Synthesis and Nicotinic Receptor Activity of Chemical Space Analogs of N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) and 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromo..., in J. Med. Chem., not known yet(not known ).

Collaboration

Group / person Country
Types of collaboration
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
BioMedical Transporters 2011, Bioparadigms "Membrane Transporters in Drug Discovery" Talk given at a conference BioMedical Transporters 2011, Bioparadigms "Membrane Transporters in Drug Discovery" 07.08.2011 Grindelwald, Switzerland, Switzerland Schwartz Julian; Reymond Jean-Louis; Visini Ricardo; Blum Lorenz; Kadam Rameshwar;


Knowledge transfer events



Self-organised

Title Date Place
Tag der Offenen Tür am DCB Bern 18.06.2011 Freiestrasse 3, Bern, Switzerland

Associated projects

Number Title Start Funding scheme
146363 Chemical Space as a Source for New Drugs 01.05.2013 Project funding (Div. I-III)
146363 Chemical Space as a Source for New Drugs 01.05.2013 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)
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)

Abstract

Drug discovery is vital to modern medicine. In recent years drug discovery has hit two serious barriers to further progress. One is biological, namely the lack of new "druggable" targets, which reflects slow progress in exploring the human genome and proteome and its relationship to diseases. The second is chemical, namely the apparent lack of innovative chemical structures, so-called chemotypes, which are key to the ability to develop new chemical entities. Our project addresses this chemical problem by an exhaustive enumeration approach. In recent years, we have reported the databases GDB-11 and GDB-13, which enumerate the content of the possible chemical space up to 11 respectively 13 atoms. These databases contain small organic building blocks and drug molecules. This proposal aims at extending GDB, as well as at searching for new small molecule drugs in GDB. The drug discovery part uses virtual screening to identify "virtual hits", i.e. small molecules showing high activity scores in silico. Some of these virtual hits are then synthesized and tested. Our efforts focus on molecules that are structurally new yet synthetically accessible. The projects concern receptors in the central nervous system (CNS), where small organic molecules are particularly useful, such as ionotropic glutamate receptors, which are the major excitatory neurotransmitter receptors in the mammalian CNS and play a central role in brain function and in neuro-degenerative disease, and the nicotinic acetyl choline receptor, where small molecule ligands are of interest for subtype characterization.
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