Selective flexibility of side-chain residues improves VEGFR-2 docking score usi...

• Autor(es): Abreu, Rui M.V. ; Froufe, Hugo J.C. ; Queiroz, Maria João R.P. ; Ferreira, Isabel C.F.R.
• Data: 2012
• Identificador Persistente: http://hdl.handle.net/10198/7377
• Origem: Biblioteca Digital do IPB
• Assunto(s): aa residue flexibility; Docking; Drug design; VEGFR-2; Virtual screening
• Tipo de Documento: Artigo
• Idioma: Inglês

Descrição

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 antiangiogenic 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.