title: Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA.
abstract: Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyanofluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure-activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations. We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes.
authors.affiliation: Departamento de Química, Facultad de Ciencias Exactas, Universidad Andres Bello, Avenida República 252, Santiago, Chile.|Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
authors.forename: Karel
authors.initials: K
authors.lastname: Mena-Ulecia
authors.affiliation: Departamento de Química, Facultad de Ciencias Exactas, Universidad Andres Bello, Avenida República 252, Santiago, Chile.
authors.forename: William
authors.initials: W
authors.lastname: Tiznado
authors.affiliation: Centro de Bioinformática y Simulación Molecular, Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, Casilla 721, Talca, Chile.
authors.forename: Julio
authors.initials: J
authors.lastname: Caballero
mesh_terms: D000991:Antithrombins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D046911:Macromolecular Substances / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000991:Antithrombins; D046911:Macromolecular Substances; D013917:Thrombin