title: Selective flexibility of side-chain residues improves VEGFR-2 docking score using AutoDock Vina.
abstract: Selective side-chain residue flexibility is an option available on AutoDock Vina docking software. This approach is promising as it attempts to provide a more realistic ligand-protein interaction environment without an unmanageable increase in computer processing time. However, studies validating this approach are still scarce. VEGFR-2 (vascular endothelial growth factor receptor 2), a known protein target for anti-angiogenic agents, was used in this study. Four residues located in the VEGFR-2 kinase site were selected and made flexible: Lys868, Glu885, Cys919, and Asp1046. The docking scores for all possible combinations of flexible residues were compared to the docking scores using a rigid conformation. The best overall docking scores were obtained using the Glu885 flexible conformation, with Pearson and Spearman rank correlation values of 0.568 and 0.543, respectively, and a 51% increase in processing time. Using different VEGFR-2 crystal structures, a similar trend was observed with the Glu885 flexible conformation presenting best scores. This study demonstrates that careful use of selective side-chain residue flexibility can improve AutoDock Vina docking score accuracy, without a significant increase in processing time. This methodology can be a valuable tool in drug design projects using VEGFR-2 but will also probably be useful if applied to other protein targets.
authors.affiliation: CIMO-ESA, Instituto Politécnico de Bragança, Campus de Sta Apolónia, Apartado 1172, 5301-855 Bragança, Portugal. ruiabreu@ipb.pt
authors.forename: Rui M V
authors.initials: RM
authors.lastname: Abreu
authors.forename: Hugo J C
authors.initials: HJ
authors.lastname: Froufe
authors.forename: Maria-João R P
authors.initials: MJ
authors.lastname: Queiroz
authors.forename: Isabel C F R
authors.initials: IC
authors.lastname: Ferreira
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D012984:Software; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2