Computational Drug Discovery and Design

Chapter 9

Molecular Dynamics as a Tool for Virtual Ligand Screening

Gre ́gory Menchon, Laurent Maveyraud, and Georges Czaplicki

Abstract

Rational drug design is essential for new drugs to emerge, especially when the structure of a target protein
or catalytic enzyme is known experimentally. To that purpose, high-throughput virtual ligand screening
campaigns aim at discovering computationally new binding molecules or fragments to inhibit a particular
protein interaction or biological activity. The virtual ligand screening process often relies on docking
methods which allow predicting the binding of a molecule into a biological target structure with a correct
conformation and the best possible affinity. The docking method itself is not sufficient as it suffers from
several and crucial limitations (lack of protein flexibility information, no solvation effects, poor scoring
functions, and unreliable molecular affinity estimation).
At the interface of computer techniques and drug discovery, molecular dynamics (MD) allows introdu-
cing protein flexibility before or after a docking protocol, refining the structure of protein–drug complexes
in the presence of water, ions and even in membrane-like environments, and ranking complexes with more
accurate binding energy calculations. In this chapter we describe the up-to-date MD protocols that are
mandatory supporting tools in the virtual ligand screening (VS) process. Using docking in combination
with MD is one of the best computer-aided drug design protocols nowadays. It has proved its efficiency
through many examples, described below.

Key wordsAffinity, Clustering, Docking, Drug design, Interaction energy, Molecular dynamics,

Protein–ligand complex, Virtual screening

1 Introduction

Virtual ligand screening has become an important tool in the world

of rational drug design and early development process in the last

decades, but remains a very challenging task. The complexity of

such a research requires more and more accurate and sophisticated

computational techniques and material to achieve a successful

active and biologically relevant compound discovery program.

In contrast with an experimental high-throughput assay,

knowledge of the experimental 3D structure of a target protein or

enzyme (or at least a high quality model based on homologous

proteins) is a prerequisite to a rational approach in drug discovery.

This information is brought through the well-known NMR, X-ray

Mohini Gore and Umesh B. Jagtap (eds.),Computational Drug Discovery and Design, Methods in Molecular Biology, vol. 1762,
https://doi.org/10.1007/978-1-4939-7756-7_9,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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