title: 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 queries-and combinations thereof-in 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 structures--in conjunction with logic operations on interactions and docking constraints derived from protein structure--is 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 according to the similarity of their interaction pattern with known ligands, thereby--to some extent--outweighing the deficiencies of simple scoring functions often used in initial virtual screening.
authors.affiliation: 4SC AG, Am Klopferspitz 19a, D-82152 Martinsried, Germany. markus.seifert@4sc.com
authors.forename: Markus H J
authors.initials: MH
authors.lastname: Seifert
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D015774:Ganciclovir / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012984:Software; D013936:Thymidine / Q000737:chemistry / Q000378:metabolism; D013937:Thymidine Kinase / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D013937:Thymidine Kinase; D015774:Ganciclovir; D013936:Thymidine