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Solvents to Fragments to Drugs: MD Applications in Drug Design

1
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
2
IQUIBICEN/UBA-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
3
Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain
4
Faculty of Pharmacy and Institute of Biomedicine (IBUB), University of Barcelona, Avgda. Diagonal 643, 08028 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Both authors contributed equally.
Academic Editors: Rebecca Wade and Outi Salo-Ahen
Molecules 2018, 23(12), 3269; https://doi.org/10.3390/molecules23123269
Received: 15 October 2018 / Revised: 2 December 2018 / Accepted: 3 December 2018 / Published: 11 December 2018
(This article belongs to the Special Issue Molecular Modeling in Drug Design)
Simulations of molecular dynamics (MD) are playing an increasingly important role in structure-based drug discovery (SBDD). Here we review the use of MD for proteins in aqueous solvation, organic/aqueous mixed solvents (MDmix) and with small ligands, to the classic SBDD problems: Binding mode and binding free energy predictions. The simulation of proteins in their condensed state reveals solvent structures and preferential interaction sites (hot spots) on the protein surface. The information provided by water and its cosolvents can be used very effectively to understand protein ligand recognition and to improve the predictive capability of well-established methods such as molecular docking. The application of MD simulations to the study of the association of proteins with drug-like compounds is currently only possible for specific cases, as it remains computationally very expensive and labor intensive. MDmix simulations on the other hand, can be used systematically to address some of the common tasks in SBDD. With the advent of new tools and faster computers we expect to see an increase in the application of mixed solvent MD simulations to a plethora of protein targets to identify new drug candidates. View Full-Text
Keywords: molecular dynamics; cosolvent molecular dynamics; drug design; fragment screening; docking molecular dynamics; cosolvent molecular dynamics; drug design; fragment screening; docking
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MDPI and ACS Style

Defelipe, L.A.; Arcon, J.P.; Modenutti, C.P.; Marti, M.A.; Turjanski, A.G.; Barril, X. Solvents to Fragments to Drugs: MD Applications in Drug Design. Molecules 2018, 23, 3269.

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