Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA

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dc.contributor.authorMena-Ulecia, K.
dc.contributor.authorTiznado, W.
dc.contributor.authorCaballero, J.
dc.date.accessioned2017-08-17T20:32:00Z
dc.date.available2017-08-17T20:32:00Z
dc.date.issued2015-11
dc.descriptionIndexación: Web of Science; Scopus.es_CL
dc.description.abstractNon-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyano-fluorophenylacetamide, 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. © 2015 Mena-Ulecia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.es_CL
dc.description.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142774
dc.identifier.citationPLoS ONE. Volume 10, Issue 11, 1 November 2015, Article number e0142774es_CL
dc.identifier.issn1932-6203
dc.identifier.otherhttps://doi.org/10.1371/journal.pone.0142774
dc.identifier.urihttp://repositorio.unab.cl/xmlui/handle/ria/3967
dc.language.isoenes_CL
dc.publisherPublic Library of Sciencees_CL
dc.subjectThrombin inhibitores_CL
dc.subjectAntithrombines_CL
dc.subjectMacromoleculees_CL
dc.subjectThrombines_CL
dc.titleStudy of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSAes_CL
dc.typeArtículoes_CL
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