Project

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

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

Active participation

Self-organised

Number	Title	Start	Funding scheme

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.