IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
artículos
Título:
Cosolvent-Based Protein Pharmacophore for Ligand Enrichment in Virtual Screening
Autor/es:
ARCON, JUAN PABLO; BURASTERO, OSVALDO; MARTI, MARCELO A.; DEFELIPE, LUCAS A.; MODENUTTI, CARLOS P.; TURJANSKI, ADRIAN G.; LOPEZ, ELIAS D.; BARRIL, XAVIER; ARCON, JUAN PABLO; BURASTERO, OSVALDO; MARTI, MARCELO A.; DEFELIPE, LUCAS A.; MODENUTTI, CARLOS P.; TURJANSKI, ADRIAN G.; LOPEZ, ELIAS D.; BARRIL, XAVIER
Revista:
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Editorial:
AMER CHEMICAL SOC
Referencias:
Año: 2019 vol. 59 p. 3572 - 3583
ISSN:
1549-9596
Resumen:
Virtual screening of large compound databases,looking for potential ligands of a target protein, is a major toolin computer-aided drug discovery. Throughout the years,different techniques such as similarity searching, pharmacophore matching, or molecular docking have been applied withthe aim of finding hit compounds showing appreciable affinity.Molecular dynamics simulations in mixed solvents have beenshown to identify hot spots relevant for protein−druginteraction, and implementations based on this knowledgewere developed to improve pharmacophore matching of small molecules, binding free-energy estimations, and dockingperformance in terms of pose prediction. Here, we proved in a retrospective manner that cosolvent-derived pharmacophoresfrom molecular dynamics (solvent sites) improve the performance of docking-based virtual screening campaigns. We applied abiased docking scheme based on solvent sites to nine relevant target proteins that have a set of known ligands or actives andcompounds that are, presumably, nonbinders (decoys). Our results show improvement in virtual screening performancecompared to traditional docking programs both at a global level, with up to 35% increase in areas under the receiver operatingcharacteristic curve, and in early stages, with up to a 7-fold increase in enrichment factors at 1%. However, the improvement inpose prediction of actives was less profound. The presented application makes use of the AutoDock Bias method and is the onlycosolvent-derived pharmacophore technique that employs its knowledge both in the ligand conformational search algorithmand the final affinity scoring for virtual screening purposes.