110
that at least 30–35% of marketed drugs suffer from low solubility
[3].
Sartans are a class of chemical compounds [angiotensin II type
1 receptor blockers (ARBs)] that hinder the detrimental hypertensive effects of angiotensin II at the AT1 receptor in a pathological
state [4]. Despite their proven beneficial action against hypertension, sartans are characterized by high lipophilicity and violate the
Lipinski rule (MLogP >4.15). This feature negatively impacts the
absorbance, tissue penetration, and bioavailability of these
molecules.
To improve the pharmacological properties of such chemicals,
one may incorporate them into the structures of hydrophilic molecules, which form inclusion complexes with the drug and may act
as carriers for selective drug release to the active target. Cyclodextrins
have been shown to constitute proper transport systems for sartans, as they can easily accommodate these molecules into their
binding region, thus inducing favorable interactions within the
inclusion complex [5].
Computational techniques are widely used for the study of
biomolecular systems, mainly because they combine reliable predictions with high speed at a minimal cost. Computational chemistry has been successfully applied to the study of proteins, nucleic
acids, lipid bilayers, and transport systems and in the drug design
process. Therefore, it is evident that such approaches can offer significant help in the rational design of new drug formulations
[6–10].
In this work, we present the detailed computational methodology for:
1. Modeling the inclusion of sartans into cyclodextrins
2. Monitoring and analyzing the conformational evolution of the
complexes
3. Predicting the energetic properties of the complexes
In particular, we apply computational methods [i.e., molecular
docking, quantum chemistry (QM), molecular dynamics (MD),
and binding free energy calculations] for the study of conformational properties and interactions between drug irbesartan (IRB)
and hydrophilic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) as
a representative example (Fig. 1). We note that the same methodology can also be applied to any other drug:cyclodextrin system.
Besides its effectiveness on blood pressure regulation, IRB exerts
poly-pharmacologic actions against other conditions, such as diabetes and cancer, and it can be considered superior to other sartans
[11–13]. However, IRB deviates from an excellent pharmaceutical
profile as it presents minimal hydrophilicity and low bioavailability
(approx. 65–70%) [14].
Georgios Leonis et al.
that at least 30–35% of marketed drugs suffer from low solubility
[3].
Sartans are a class of chemical compounds [angiotensin II type
1 receptor blockers (ARBs)] that hinder the detrimental hypertensive effects of angiotensin II at the AT1 receptor in a pathological
state [4]. Despite their proven beneficial action against hypertension, sartans are characterized by high lipophilicity and violate the
Lipinski rule (MLogP >4.15). This feature negatively impacts the
absorbance, tissue penetration, and bioavailability of these
molecules.
To improve the pharmacological properties of such chemicals,
one may incorporate them into the structures of hydrophilic molecules, which form inclusion complexes with the drug and may act
as carriers for selective drug release to the active target. Cyclodextrins
have been shown to constitute proper transport systems for sartans, as they can easily accommodate these molecules into their
binding region, thus inducing favorable interactions within the
inclusion complex [5].
Computational techniques are widely used for the study of
biomolecular systems, mainly because they combine reliable predictions with high speed at a minimal cost. Computational chemistry has been successfully applied to the study of proteins, nucleic
acids, lipid bilayers, and transport systems and in the drug design
process. Therefore, it is evident that such approaches can offer significant help in the rational design of new drug formulations
[6–10].
In this work, we present the detailed computational methodology for:
1. Modeling the inclusion of sartans into cyclodextrins
2. Monitoring and analyzing the conformational evolution of the
complexes
3. Predicting the energetic properties of the complexes
In particular, we apply computational methods [i.e., molecular
docking, quantum chemistry (QM), molecular dynamics (MD),
and binding free energy calculations] for the study of conformational properties and interactions between drug irbesartan (IRB)
and hydrophilic 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) as
a representative example (Fig. 1). We note that the same methodology can also be applied to any other drug:cyclodextrin system.
Besides its effectiveness on blood pressure regulation, IRB exerts
poly-pharmacologic actions against other conditions, such as diabetes and cancer, and it can be considered superior to other sartans
[11–13]. However, IRB deviates from an excellent pharmaceutical
profile as it presents minimal hydrophilicity and low bioavailability
(approx. 65–70%) [14].
Georgios Leonis et al.