109
Thomas Mavromoustakos et al. (eds.), Supramolecules in Drug Discovery and Drug Delivery: Methods and Protocols,
Methods in Molecular Biology, vol. 2207, https://doi.org/10.1007/978-1-0716-0920-0_9,
© Springer Science+Business Media, LLC, part of Springer Nature 2021
Chapter 9
Molecular Dynamics Protocols for the Study
of Cyclodextrin Drug Delivery Systems
Georgios Leonis, Dimitrios Ntountaniotis, Eirini Christodoulou,
and Thomas Mavromoustakos
Abstract
Hypertension treatment is a current therapeutic priority as there is a constantly increasing part of the
population that suffers from this risk factor, which may lead to cardiovascular and encephalic episodes and
eventually to death. A number of marketed medicines consist of active ingredients that may be relatively
potent; however, there is plenty of room to enhance their pharmacological profile and therapeutic index
by improving specific physicochemical properties. In this work, we focus on a class of blood pressure regulators, called sartans, and we present the computational scheme for the pharmacological improvement of
irbesartan (IRB) as a representative example. IRB has been shown to exert increased pharmacological
action compared with other sartans, but it appears to be highly lipophilic and violates Lipinski rule (MLogP
>4.15). To circumvent this drawback, proper hydrophilic molecules, such as cyclodextrins, can be used as
drug carriers. This chapter describes the combinatory use of computational methods, namely molecular
docking, quantum mechanics, molecular dynamics, and free energy calculations, to study the interactions
and the energetic contributions that govern the IRB:cyclodextrin association. We provide a detailed computational protocol, which aims to assist the improvement of the pharmacological properties of sartans.
This protocol can also be applied to any other drug molecule with diminished hydrophilic character.
Key words Sartans, Irbesartan, 2-Hydroxypropyl-β-cyclodextrin, Blood pressure regulation,
Hypertension, Molecular modeling, Molecular dynamics, Pharmacological enhancement
1 Introduction
The pharmaceutical industry aims at the development of effective
medications with the lowest safety risk. However, this is not an easy
task, since efficacy is often compromised for diminished side effects.
Several marketed medicines contain active compounds, which possess specific physicochemical properties that deviate from an optimal pharmacological profile. The main reasons for poor drug
performance are the low solubility and permeability, fast metabolism and excretion, and also undesired side effects [1, 2]. It is noted
Thomas Mavromoustakos et al. (eds.), Supramolecules in Drug Discovery and Drug Delivery: Methods and Protocols,
Methods in Molecular Biology, vol. 2207, https://doi.org/10.1007/978-1-0716-0920-0_9,
© Springer Science+Business Media, LLC, part of Springer Nature 2021
Chapter 9
Molecular Dynamics Protocols for the Study
of Cyclodextrin Drug Delivery Systems
Georgios Leonis, Dimitrios Ntountaniotis, Eirini Christodoulou,
and Thomas Mavromoustakos
Abstract
Hypertension treatment is a current therapeutic priority as there is a constantly increasing part of the
population that suffers from this risk factor, which may lead to cardiovascular and encephalic episodes and
eventually to death. A number of marketed medicines consist of active ingredients that may be relatively
potent; however, there is plenty of room to enhance their pharmacological profile and therapeutic index
by improving specific physicochemical properties. In this work, we focus on a class of blood pressure regulators, called sartans, and we present the computational scheme for the pharmacological improvement of
irbesartan (IRB) as a representative example. IRB has been shown to exert increased pharmacological
action compared with other sartans, but it appears to be highly lipophilic and violates Lipinski rule (MLogP
>4.15). To circumvent this drawback, proper hydrophilic molecules, such as cyclodextrins, can be used as
drug carriers. This chapter describes the combinatory use of computational methods, namely molecular
docking, quantum mechanics, molecular dynamics, and free energy calculations, to study the interactions
and the energetic contributions that govern the IRB:cyclodextrin association. We provide a detailed computational protocol, which aims to assist the improvement of the pharmacological properties of sartans.
This protocol can also be applied to any other drug molecule with diminished hydrophilic character.
Key words Sartans, Irbesartan, 2-Hydroxypropyl-β-cyclodextrin, Blood pressure regulation,
Hypertension, Molecular modeling, Molecular dynamics, Pharmacological enhancement
1 Introduction
The pharmaceutical industry aims at the development of effective
medications with the lowest safety risk. However, this is not an easy
task, since efficacy is often compromised for diminished side effects.
Several marketed medicines contain active compounds, which possess specific physicochemical properties that deviate from an optimal pharmacological profile. The main reasons for poor drug
performance are the low solubility and permeability, fast metabolism and excretion, and also undesired side effects [1, 2]. It is noted