Chapter 14
Molecular Dynamics Simulation Techniques as Tools in Drug
Discovery and Pharmacology: A Focus on Allosteric Drugs
Chiara Bianca Maria Platania and Claudio Bucolo
Abstract
Allosteric drugs are ligands that when bound to an allosteric site modify the conformational state of the
pharmacological target, leading then to a modification of functional response upon binding of the
endogenous ligand. Pharmacological targets are defined as biological entities, to which a ligand/drug
binds and leads to a functional effect. Pharmacological targets can be proteins or nucleic acids. Computational approaches such as molecular dynamics (MD) sped up discovery and identification of allosteric
binding sites and allosteric ligands. Classical all-atom and hybrid classical/quantum MD simulations can
be generalized as simulation techniques aimed at analysis of atoms and molecular motion. Main limitations
of MD simulations are related to high computational costs, that in turn limit the conformational sampling
of biological systems. Indeed, other techniques have been developed to overcome limitations of MD,
such as enhanced sampling MD simulations. In this chapter, classical MD and enhanced sampling MD
simulations will be described, along with their application to drug discovery, with a focus on allosteric
drugs.
Key words Allosteric drugs, Molecular dynamics, Drug discovery, Pharmacology
1 Introduction
1.1 Allosteric Drugs
Pharmacological target function could be modulated by drugs that
bind to an orthosteric pocket or an allosteric pocket. Orthosteric
drugs competitively bind to the same pocket of the endogenous
ligand, working as competitive agonists or antagonists; while allosteric drugs bind to a pocket different from the orthosteric one,
leading to conformational changes and positive or negative modulation of receptor activity, upon binding of the endogenous ligand.
Positive allosteric modulators (PAM) increase the receptor functional response or decrease the EC50 of agonists or endogenous
ligand (increased endogenous ligand efficiency) (Fig. 1). The negative allosteric modulators (NAM) decrease receptor functional
response and increase agonists or endogenous ligand EC50
(decreased endogenous ligand efficiency) (Fig. 1). Russinov &
Luisa Di Paola and Alessandro Giuliani (eds.), Allostery: Methods and Protocols, Methods in Molecular Biology, vol. 2253,
https://doi.org/10.1007/978-1-0716-1154-8_14, © Springer Science+Business Media, LLC, part of Springer Nature 2021
245
Molecular Dynamics Simulation Techniques as Tools in Drug
Discovery and Pharmacology: A Focus on Allosteric Drugs
Chiara Bianca Maria Platania and Claudio Bucolo
Abstract
Allosteric drugs are ligands that when bound to an allosteric site modify the conformational state of the
pharmacological target, leading then to a modification of functional response upon binding of the
endogenous ligand. Pharmacological targets are defined as biological entities, to which a ligand/drug
binds and leads to a functional effect. Pharmacological targets can be proteins or nucleic acids. Computational approaches such as molecular dynamics (MD) sped up discovery and identification of allosteric
binding sites and allosteric ligands. Classical all-atom and hybrid classical/quantum MD simulations can
be generalized as simulation techniques aimed at analysis of atoms and molecular motion. Main limitations
of MD simulations are related to high computational costs, that in turn limit the conformational sampling
of biological systems. Indeed, other techniques have been developed to overcome limitations of MD,
such as enhanced sampling MD simulations. In this chapter, classical MD and enhanced sampling MD
simulations will be described, along with their application to drug discovery, with a focus on allosteric
drugs.
Key words Allosteric drugs, Molecular dynamics, Drug discovery, Pharmacology
1 Introduction
1.1 Allosteric Drugs
Pharmacological target function could be modulated by drugs that
bind to an orthosteric pocket or an allosteric pocket. Orthosteric
drugs competitively bind to the same pocket of the endogenous
ligand, working as competitive agonists or antagonists; while allosteric drugs bind to a pocket different from the orthosteric one,
leading to conformational changes and positive or negative modulation of receptor activity, upon binding of the endogenous ligand.
Positive allosteric modulators (PAM) increase the receptor functional response or decrease the EC50 of agonists or endogenous
ligand (increased endogenous ligand efficiency) (Fig. 1). The negative allosteric modulators (NAM) decrease receptor functional
response and increase agonists or endogenous ligand EC50
(decreased endogenous ligand efficiency) (Fig. 1). Russinov &
Luisa Di Paola and Alessandro Giuliani (eds.), Allostery: Methods and Protocols, Methods in Molecular Biology, vol. 2253,
https://doi.org/10.1007/978-1-0716-1154-8_14, © Springer Science+Business Media, LLC, part of Springer Nature 2021
245