RESUMO
Docking of the 5CITEP inhibitor to snapshots of a 2 ns HIV-1 integrase MD trajectory indicated a previously uncharacterized trench adjacent to the active site that intermittently opens. Further docking studies of novel ligands with the potential to bind to both regions showed greater selective affinity when able to bind to the trench. Our ranking of ligands is open to experimental testing, and our approach suggests a new target for HIV-1 therapeutics.
Assuntos
Integrase de HIV/química , Sítios de Ligação , Cristalografia por Raios X , Integrase de HIV/metabolismo , Indóis/química , Ligantes , Modelos Moleculares , Conformação Molecular , Naftalenos/química , Ligação Proteica , Relação Estrutura-Atividade , Tetrazóis/químicaAssuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Indicadores e Reagentes , Metaloproteinase 3 da Matriz/química , Metaloproteinases da Matriz/química , Metais/química , Modelos Moleculares , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
An extension of the new computational methodology for drug design, the "relaxed complex" method (J.-H. Lin, A. L. Perryman, J. R. Schames, and J. A. McCammon, Journal of the American Chemical Society, 2002, vol. 24, pp. 5632-5633), which accommodates receptor flexibility, is described. This relaxed complex method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand-enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand enzyme complexes. Rapid docking serves as an efficient initial filtering method to screen a myriad of docking modes to a limited set, and it is then followed by more accurate scoring with the MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area) approach to find the best ligand-receptor complexes. The MM/PBSA scorings consistently indicate that the calculated binding modes that are most similar to those observed in the x-ray crystallographic complexes are the ones with the lowest free energies.
Assuntos
Desenho de Fármacos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Proteínas de Ligação a Tacrolimo/química , Proteínas de Ligação a Tacrolimo/metabolismo , Algoritmos , Sítios de Ligação , Cinética , Ligantes , Modelos Moleculares , Movimento (Física) , Ligação Proteica , Estrutura Secundária de Proteína , Projetos de Pesquisa , TermodinâmicaRESUMO
A novel computational methodology for drug design that accommodates receptor flexibility is described. This "relaxed-complex" method recognizes that ligand may bind to conformations that occur only rarely in the dynamics of the receptor. We have shown that the ligand-enzyme binding modes are very sensitive to the enzyme conformations, and our approach is capable of finding the best ligand-enzyme complexes. This new method serves as the computational analog of the experimental "SAR by NMR" and "tether" methods, which permit a building block approach for constructing a very potent drug.
