Predicting Value of Binding Constants of Organic Ligands to Beta-Cyclodextrin: Application of MARSplines and Descriptors Encoded in SMILES String

Piotr Cysewski,Maciej Przybyłek

doi:10.3390/sym11070922

Piotr Cysewski, Maciej Przybyłek

Open Access

https://doi.org/10.3390/sym11070922

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Journal: Symmetry	Publication Date: Jul 15, 2019
Citations: 5	License type: CC BY 4.0

Affiliation: Nicolaus Copernicus University

Abstract

The quantitative structure–activity relationship (QSPR) model was formulated to quantify values of the binding constant (lnK) of a series of ligands to beta–cyclodextrin (β-CD). For this purpose, the multivariate adaptive regression splines (MARSplines) methodology was adopted with molecular descriptors derived from the simplified molecular input line entry specification (SMILES) strings. This approach allows discovery of regression equations consisting of new non-linear components (basis functions) being combinations of molecular descriptors. The model was subjected to the standard internal and external validation procedures, which indicated its high predictive power. The appearance of polarity-related descriptors, such as XlogP, confirms the hydrophobic nature of the cyclodextrin cavity. The model can be used for predicting the affinity of new ligands to β-CD. However, a non-standard application was also proposed for classification into Biopharmaceutical Classification System (BCS) drug types. It was found that a single parameter, which is the estimated value of lnK, is sufficient to distinguish highly permeable drugs (BCS class I and II) from low permeable ones (BCS class II and IV). In general, it was found that drugs of the former group exhibit higher affinity to β-CD then the latter group (class III and IV).

Highlights

Molecular complexes, such as inclusion adducts, clathrates, cocrystals and solvates, have been widely used in many fields, including pharmacy [1,2,3,4,5,6], agriculture [7], the food industry [1,8,9]and explosives [10,11]
It was found that a single parameter, which is the estimated value of lnK, is sufficient to distinguish highly permeable drugs (BCS class I and II) from low permeable ones (BCS class II and IV)
The most commonly used compounds in pharmaceutical formulations belonging to this class are alpha- (α-CD), beta- (β-CD), gamma- (γ-CD) cyclodextrins and their analogues such as

Summary

Introduction

Molecular complexes, such as inclusion adducts, clathrates, cocrystals and solvates, have been widely used in many fields, including pharmacy [1,2,3,4,5,6], agriculture [7], the food industry [1,8,9]and explosives [10,11]. Molecular complexes, such as inclusion adducts, clathrates, cocrystals and solvates, have been widely used in many fields, including pharmacy [1,2,3,4,5,6], agriculture [7], the food industry [1,8,9]. In the past two decades, cyclodextrins (CDs) have been one of the most extensively studied complexation agents, especially as pharmaceutical excipients [12,13,14,15]. The main criterion used for distinguishing different CDs (α-CD, β-CD and γ-CD) corresponds to six, seven and eight D-glucopyranose units, respectively. These excipients have been used for all main types of drug delivery systems (oral, nasal, rectal, dermal, ocular, parenteral) [13,21]

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