Publicação
Selective flexibility of side-chain residues improves VEGFR-2 docking score using autodock vina
| Resumo: | 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. |
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| Autores principais: | Abreu, Rui M. V. |
| Outros Autores: | Froufe, Hugo J. C.; Queiroz, Maria João R. P.; Ferreira, Isabel C. F. R. |
| Assunto: | Drug design Virtual screening Aa residues flexibility VEGFR-2 aa residue flexibility docking |
| Ano: | 2012 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | 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. |
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