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Artículo

Cosolvent-Based Protein Pharmacophore for Ligand Enrichment in Virtual Screening

Arcon, Juan PabloIcon ; Defelipe, Lucas AlfredoIcon ; Lopez, Elias DanielIcon ; Burastero, OsvaldoIcon ; Modenutti, Carlos PabloIcon ; Barril, Xavier; Marti, Marcelo AdrianIcon ; Turjanski, AdrianIcon
Fecha de publicación: 08/2019
Editorial: American Chemical Society
Revista: Journal of Chemical Information and Modeling
ISSN: 1549-9596
e-ISSN: 1520-5142
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Biológicas

Resumen

Virtual screening of large compound databases, looking for potential ligands of a target protein, is a major tool in computer-aided drug discovery. Throughout the years, different techniques such as similarity searching, pharmacophore matching, or molecular docking have been applied with the aim of finding hit compounds showing appreciable affinity. Molecular dynamics simulations in mixed solvents have been shown to identify hot spots relevant for protein-drug interaction, and implementations based on this knowledge were developed to improve pharmacophore matching of small molecules, binding free-energy estimations, and docking performance in terms of pose prediction. Here, we proved in a retrospective manner that cosolvent-derived pharmacophores from molecular dynamics (solvent sites) improve the performance of docking-based virtual screening campaigns. We applied a biased docking scheme based on solvent sites to nine relevant target proteins that have a set of known ligands or actives and compounds that are, presumably, nonbinders (decoys). Our results show improvement in virtual screening performance compared to traditional docking programs both at a global level, with up to 35% increase in areas under the receiver operating characteristic curve, and in early stages, with up to a 7-fold increase in enrichment factors at 1%. However, the improvement in pose prediction of actives was less profound. The presented application makes use of the AutoDock Bias method and is the only cosolvent-derived pharmacophore technique that employs its knowledge both in the ligand conformational search algorithm and the final affinity scoring for virtual screening purposes.
Palabras clave: AutodockBias , Cosolvents , Virtual Screening , Molecular Dynamics
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/121819
URL: https://pubs.acs.org/doi/abs/10.1021/acs.jcim.9b00371
DOI: http://dx.doi.org/10.1021/acs.jcim.9b00371
Colecciones
Articulos(IQUIBICEN)
Articulos de INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CS. EXACTAS Y NATURALES
Citación
Arcon, Juan Pablo; Defelipe, Lucas Alfredo; Lopez, Elias Daniel; Burastero, Osvaldo; Modenutti, Carlos Pablo; et al.; Cosolvent-Based Protein Pharmacophore for Ligand Enrichment in Virtual Screening; American Chemical Society; Journal of Chemical Information and Modeling; 59; 8; 8-2019; 3572-3583
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