ProPose: Steered Virtual Screening by Simultaneous Protein—Ligand Docking and Ligand—Ligand Alignment.

Abstract

The ‘model-free' screening engine ProPose implements a general method for performing simultaneous protein−ligand docking, ligand−ligand alignment, pharmacophore queriesand combinations thereofin order to incorporate a priori information into screening protocols. In this manuscript we describe a case study on herpes simplex virus thymidine kinase, an important antiviral drug target, where we evaluate different approaches for handling a specific type of a priori information, i.e., multiple target structures. We demonstrate that a simultaneous alignment on two target structuresin conjunction with logic operations on interactions and docking constraints derived from protein structureis an effective means of (i) improving the enrichment of chemical substructures that are compatible with the a priori known ligands, (ii) ensuring the steric fit into the target protein, and (iii) handling target flexibility. The combination of ligand- and receptor-based methods steers the virtual screening by ranking molecules ac...