Computational Drug Discovery and Design

Chapter 6

Molecular Dynamics Simulation and Prediction

of Druggable Binding Sites

Tianhua Feng and Khaled Barakat

Abstract

Binding site identification and druggability evaluation are two essential steps in structure-based drug
design. A druggable binding site tends to have high binding affinity to drug-like molecules. Predicting
such sites can have a significant impact on a drug design campaign. This chapter focuses on summarizing the
different methods that are used to predict druggable binding sites. The chapter also discusses the impor-
tance of including protein flexibility in the search process and the use of molecular dynamics simulations to
address this aspect. Case studies from the literature are also summarized and discussed. We hope that this
chapter would provide an overview on the different methods employed in binding site identification
evaluation.

Key wordsConformational ensemble, Cosolvent molecular dynamic simulation, Druggability, Hot

spot, Protein flexibility

1 Introduction

Proteins are dynamical entities in nature. They interact with each

other or with small molecule compounds to execute their function

or to transfer a signal [1]. These interactions usually take place

through hot spots on the surface of the proteins [2]. In many

cases these hot spots cluster into one region, forming a binding

site, which can specifically fit the interacting partner. These binding

sites have been always considered as attractive targets to develop

target-specific drugs [3–5]. However, not every binding site is

suitable to develop a drug. One should think about the druggability

of a binding site prior to searching for a compound that can fit

within the site [6]. Druggability of binding sites emerged in the

recent years [7] and was first defined as the ability of a protein

linked to a particular disease to bind a small drug-like molecule with

high affinity and specificity [8, 9].

Although using an automated approach to predict the “drugg-

ability” of a binding site is still difficult [10], computational

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_6,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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