45
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_5,
© Springer Science+Business Media, LLC, part of Springer Nature 2021
Chapter 5
Study of Candesartan Cilexetil: 2-Hydroxypropyl-βCyclodextrin Interactions: A Computational Approach Using
Steered Molecular Dynamics Simulations
Sofia Kiriakidi and Thomas Mavromoustakos
Abstract
Cyclodextrins (CDs) are widely used in the pharmaceutical industry as transporters of lipophilic drugs due
to their amphiphilic nature. The detailed study of the molecular interactions of drug complexes with CDs
is very important in designing the best formulation for the transportation of lipophilic drugs. The drug:
CD binding should be strong enough so that the complex is stable in the aquatic environment of the
extracellular fluids, but also not very strong in order for the drug to be capable for being released in the
proximity of the target receptor. In a recent study, we investigated the ΔG of binding between the commercially available, nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-B-CD) and the antihypertensive drug
candesartan cilexetil (CC), with the use of steered (or biased) molecular dynamics (sMD) and umbrella
sampling method. This chapter describes comprehensively how to perform sMD and umbrella sampling in
order to calculate the ΔG binding of CC to the 2-HP-B-CD.
Key words Steered MD, ΔG binding , Umbrella sampling, Biased MD, Candesartan, Hypertension,
Lipophilicity, Drug transporter
1 Introduction
Candesartan cilexetil (CC, commercial name Atacand) is a prodrug, which is rapidly converted to the active drug, candesartan
(CAN), by ester hydrolysis during absorption from the gastrointestinal area of the human body. Due to the highly lipophilic nature
of CC, the drug’s bioavailability is only 15% after oral administration [1]. The use of cyclodextrins (CDs) as drug carriers is investigated in order to increase CAN’s bioavailability [2, 3], by increasing
its aqueous solubility before interacting with the membrane receptor system, as depicted in Fig. 1. In our recent study [4], we investigated the ΔG of binding between the commercially available,
nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-B-CD) [5, 6]
and the antihypertensive drug candesartan cilexetil (CC), with the
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_5,
© Springer Science+Business Media, LLC, part of Springer Nature 2021
Chapter 5
Study of Candesartan Cilexetil: 2-Hydroxypropyl-βCyclodextrin Interactions: A Computational Approach Using
Steered Molecular Dynamics Simulations
Sofia Kiriakidi and Thomas Mavromoustakos
Abstract
Cyclodextrins (CDs) are widely used in the pharmaceutical industry as transporters of lipophilic drugs due
to their amphiphilic nature. The detailed study of the molecular interactions of drug complexes with CDs
is very important in designing the best formulation for the transportation of lipophilic drugs. The drug:
CD binding should be strong enough so that the complex is stable in the aquatic environment of the
extracellular fluids, but also not very strong in order for the drug to be capable for being released in the
proximity of the target receptor. In a recent study, we investigated the ΔG of binding between the commercially available, nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-B-CD) and the antihypertensive drug
candesartan cilexetil (CC), with the use of steered (or biased) molecular dynamics (sMD) and umbrella
sampling method. This chapter describes comprehensively how to perform sMD and umbrella sampling in
order to calculate the ΔG binding of CC to the 2-HP-B-CD.
Key words Steered MD, ΔG binding , Umbrella sampling, Biased MD, Candesartan, Hypertension,
Lipophilicity, Drug transporter
1 Introduction
Candesartan cilexetil (CC, commercial name Atacand) is a prodrug, which is rapidly converted to the active drug, candesartan
(CAN), by ester hydrolysis during absorption from the gastrointestinal area of the human body. Due to the highly lipophilic nature
of CC, the drug’s bioavailability is only 15% after oral administration [1]. The use of cyclodextrins (CDs) as drug carriers is investigated in order to increase CAN’s bioavailability [2, 3], by increasing
its aqueous solubility before interacting with the membrane receptor system, as depicted in Fig. 1. In our recent study [4], we investigated the ΔG of binding between the commercially available,
nontoxic 2-hydroxypropyl-β-cyclodextrin (2-HP-B-CD) [5, 6]
and the antihypertensive drug candesartan cilexetil (CC), with the