RESUMEN
A novel shape-based method has been developed for overlaying a series of molecule surfaces into a common reference frame. The surfaces are represented by a set of circular patches of approximately constant curvature. Two molecules are overlaid using a clique-detection algorithm to find a set of patches in the two surfaces that correspond, and overlaying the molecules so that the similar patches on the two surfaces are coincident. The method is thus able to detect areas of local, rather than global, similarity. A consensus overlay for a group of molecules is performed by examining the scores of all pairwise overlays and performing a set of overlays with the highest scores. The utility of the method has been examined by comparing the overlaid and experimental configurations of 4 sets of molecules for which there are X-ray crystal structures of the molecules bound to a protein active site. Results for the overlays are generally encouraging. Of particular note is the correct prediction of the 'reverse orientation' for ligands binding to human rhinovirus coat protein HRV14.
Asunto(s)
Cápside/química , Diseño de Fármacos , Inhibidores de Proteasas/química , Termolisina/antagonistas & inhibidores , Simulación por Computador , Cristalografía por Rayos X , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/farmacología , Conformación Proteica , Rhinovirus , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
PURPOSE: To study oral absorption and brain penetration as a function of polar molecular surface area. METHODS: Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies. RESULTS: A linear relationship between brain penetration and dynamic polar surface area (A2) was found (n = 45, R = 0.917, F1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 A2. They can be tailored to brain penetration by decreasing the polar surface to <60-70 A2. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules. CONCLUSIONS: The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.
Asunto(s)
Barrera Hematoencefálica/efectos de los fármacos , Absorción Intestinal/efectos de los fármacos , Preparaciones Farmacéuticas/química , Animales , Encéfalo/metabolismo , Fármacos del Sistema Nervioso Central/química , Fármacos del Sistema Nervioso Central/farmacología , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Masculino , Conformación Molecular , Farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Propiedades de SuperficieRESUMEN
A set of 32 known thrombin inhibitors representing different chemical classes has been used to evaluate the performance of two implementations of incremental construction algorithms for flexible molecular docking: DOCK 4.0 and FlexX 1.5. Both docking tools are able to dock 10-35% of our test set within 2 A of their known, bound conformations using default sampling and scoring parameters. Although flexible docking with DOCK or FlexX is not able to reconstruct all native complexes, it does offer a significant improvement over rigid body docking of single, rule-based conformations, which is still often used for docking of large databases. Docking of sets of multiple conformers of each inhibitor, obtained with a novel protocol for diverse conformer generation and selection, yielded results comparable to those obtained by flexible docking. Chemical scoring, which is an empirically modified force field scoring method implemented in DOCK 4.0, outperforms both interaction energy scoring by DOCK and the Böhm scoring function used by FlexX in rigid and flexible docking of thrombin inhibitors. Our results indicate that for reliable docking of flexible ligands the selection of anchor fragments, conformational sampling and currently available scoring methods still require improvement.