Representation of target-bound drugs by computed conformers: implications for conformational libraries

Background: The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. Results: Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space. A number of up to...

• Type: Journal
• Year: 2006
• Where: BMCBI
• Authors: Stefan Günther, Christian Senger, Elke Michalsky, Andrean Goede, Robert Preissner
• Keywords: BMCBI 2006, Conformational Space, Drug, Suitable Lead Compounds