Authors: H. Merlitz and W. Wenzel
Affilation: Forschungszentrum Karlsruhe, Germany
Pages: 23 - 26
Keywords: receptor ligand docking, in silico screening flexible receptors
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.