Creating Maps of the Ligand Binding Landscape for Kinetics-Based Drug Discovery.

Autor:	Dixon T; Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI, USA.; Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, USA., Lotz SD; Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI, USA.; Roivant Sciences, New York, NY, USA., Dickson A; Department of Biochemistry & Molecular Biology, Michigan State University, East Lansing, MI, USA. alexrd@msu.edu.; Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, MI, USA. alexrd@msu.edu.
Jazyk:	angličtina
Zdroj:	Methods in molecular biology (Clifton, N.J.) [Methods Mol Biol] 2022; Vol. 2385, pp. 325-334.
DOI:	10.1007/978-1-0716-1767-0_15
Abstrakt:	Simulations of ligand-protein interactions can be very useful for drug design and to gain biological insight. Full pathways of ligand-protein binding can be used to get information about ligand binding transition states, which form the rate-limiting step of the binding and release processes. However, these simulations are typically limited by the presence of large energy barriers that separate stable poses of interest. Here we describe a simulation protocol for exploring and analyzing landscapes of ligand-protein interactions that makes use of molecular docking, enhanced molecular simulation with the weighted ensemble algorithm, and network analysis. It can be accomplished using a modest cluster of graphics processing units and freely accessible software. This protocol focuses on the construction and analysis of a network model of ligand binding poses and provides links to resources that describe the other steps in more detail. The end result of this protocol is a map of the ligand-protein binding landscape that identifies transition states of the ligand binding pathway, as well as alternative bound poses that could be stabilized with modifications to the ligand. (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze:	MEDLINE
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