Merlitz H., Wenzel W.
Forschungszentrum Karlsruhe, DE
Keywords: in silico screening flexible receptors, receptor ligand docking
Virtual screening of chemical databases to targets of known three-dimensional structure is developing into an increasingly reliable method for finding new lead candidates in drug development. Both better scoring functions and novel docking strategies contribute to this trend, although no completely satisfying approach has been established yet. This is not surprising since the approximations which are needed to achieve a reasonable screening rates impose significant restrictions on the virtual representation of the physical system. Relaxation of these restrictions, such as permitting ligand or receptor flexibility, potentially increase the reliability of the scoring process, but come at a high computational cost. While ligand flexibility is now routinely considered in many atomistic in-silico screening methods, accounting for receptor flexibility still poses significant challenges. Using the thymidine kinase inhibitors as a prototypical example we document the shortcoming of rigid receptor screens in a realistic system. We then present screens with the stochastic tunneling method against a subset of up to 10000 ligands of the NCI-Open database considering increasing receptors sidechain flexibility and demonstrate an increased reliability of the screening results.
Journal: TechConnect Briefs
Volume: 1, Technical Proceedings of the 2004 NSTI Nanotechnology Conference and Trade Show, Volume 1
Published: March 7, 2004
Pages: 23 - 26
Industry sectors: Advanced Materials & Manufacturing | Medical & Biotech
Topic: Biomaterials
ISBN: 0-9728422-7-6