Selective flexibility of side-chain residues improves VEGFR-2 docking score using autodock vina

• Autor(a) principal: Abreu, Rui M. V.
• Data de Publicação: 2012
• Outros Autores: Froufe, Hugo J. C., Queiroz, Maria João R. P., Ferreira, Isabel C. F. R.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/1822/22008
• topic: Drug design; Virtual screening; Aa residues flexibility; VEGFR-2; aa residue flexibility; docking; Science & Technology

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 present in the VEGFR-2 kinase site were selected and made flexible: Lys866, Glu885, Cys917 and Asp1044. 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 Glu883 flexible conformation, with pearson and spearman rank correlation values of 0.568 and 0.543, respectively, and a 51% increase in computer processing time. Using different VEGFR-2 X-ray structures a similar trend was observed with Glu885 flexible conformation presenting the 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 computer processing time. This methodology proved to be a valuable tool in drug design when using VEGFR-2 but will also probably be useful if applied to other protein targets.