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Application of the ESMACS Binding Free Energy Protocol to a Multi‐Binding Site Lactate Dehydogenase A Ligand Dataset

Wright, DW; Husseini, F; Wan, S; Meyer, C; van Vlijmen, H; Tresadern, G; Coveney, PV; (2019) Application of the ESMACS Binding Free Energy Protocol to a Multi‐Binding Site Lactate Dehydogenase A Ligand Dataset. Advanced Theory and Simulations 10.1002/adts.201900194. (In press). Green open access

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Abstract

Over the past two decades, the use of fragment‐based lead generation has become a common, mature approach to identify tractable starting points in chemical space for the drug discovery process. This approach naturally involves the study of the binding properties of highly heterogeneous ligands. Such datasets challenge computational techniques to provide comparable binding free energy estimates from different binding modes. The performance of a range of statistically robust ensemble‐based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent), is evaluated. Ligands designed to target two binding pockets in the lactate dehydogenase, a target protein, which vary in size, charge, and binding mode, are studied. When compared to experimental results, excellent statistical rankings are obtained across this highly diverse set of ligands. In addition, three approaches to account for entropic contributions are investigated: 1) normal mode analysis, 2) weighted solvent accessible surface area (WSAS), and 3) variational entropy. Normal mode analysis and WSAS correlate strongly with each other—although the latter is computationally far cheaper—but do not improve rankings. Variational entropy corrects exaggerated discrimination of ligands bound in different pockets but creates three outliers which reduce the quality of the overall ranking.

Type: Article
Title: Application of the ESMACS Binding Free Energy Protocol to a Multi‐Binding Site Lactate Dehydogenase A Ligand Dataset
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/adts.201900194
Publisher version: https://doi.org/10.1002/adts.201900194
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0/
Keywords: binding free energy calculations, fragment‐based drug design, molecular dynamics, molecular mechanics Poisson–Boltzmann surface area (MMPBSA)
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10086549
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