QSAR Study of α-Glucosidase Inhibitors for Benzimidazole Bearing Bis-Schiff Bases Using CoMFA, CoMSIA, and Molecular Docking

QSAR Study of α-Glucosidase Inhibitors for Benzimidazole Bearing Bis-Schiff Bases Using CoMFA, CoMSIA, and Molecular Docking

Ayoub Khaldan, Soukaina Bouamrane, Reda El-Mernissi, Khalil El Khatabi, Ilham Aanouz, Abderrahmane Aggoram, Abdelouahid Sbai, Mohammed Bouachrine, Tahar Lakhlifi
Copyright: © 2021 |Pages: 16
DOI: 10.4018/IJQSPR.2021010102
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Abstract

A new class of benzimidazoles bearing bis-Schiff bases as α-glucosidase inhibitory was studied based on the combination of two computational techniques such as 3D-QSAR and molecular docking. The CoMFA and CoMSIA QSAR models were developed from fifteen compounds in the training set and four compounds in the test set giving Q2 values of 0.587 and 0.597 respectively, and R2 values of 0.970 and 0.990 respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The CoMFA and CoMSIA contour maps allowed the authors to recognize regions where the activity can be increased or decreased by suitable substitutions. According to these contour maps they have proposed three new compounds with high predicted activities. Moreover, to confirm the stability of these newly designed molecules in the receptor with PDB: 3A4A, a Surflex-docking was applied.
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Material And Methods

Data Collection

In this study, a series of 19 molecules with reported as α-glucosidase inhibitors was taken from the literature (Rahim et al., 2019). These molecules were considered to perform the 3D-QSAR analysis; 15 molecules are selected randomly to develop the quantitative model (training set), and the 4 remaining molecules were used to test the capacity of the model (test set). The in vitro biological activities IC50 (µM) were transformed into the corresponding pIC50 values (i.e. pIC50 is the negative logarithm of IC50 (pIC50 = −log10 (IC50)). Figure 1a and Figure 1b displays the chemical structures and their values of the activity of these molecules.

Figure 1a.

Chemical structures and biological activities of benzimidazole bearing bis-Schiff bases

IJQSPR.2021010102.f01a
Figure 1b.

Chemical structures and biological activities of benzimidazole bearing bis-Schiff bases

IJQSPR.2021010102.f01b

Minimization and Alignment

SYBYL-X2.0 is a molecular modeling software used to carry out the entire 3D-QSAR (Tripos Inc., St. Louis, USA). In this analysis, every structure of nineteen benzimidazoles bearing bis-Schiff bases analogs was sketched and optimized using the SYBYL program with Tripos force field (Clark et al., 1989) Gasteiger Huckel charges and with gradient convergence criteria 0.01 kcal/mol (Purcell et al., 1967). All compounds were aligned on the common core using the simple alignment technique available in Sybyl (AbdulHameed et al., 2008). Molecule 2, which was the most active molecule in the dataset, was used as template (Figure 2).

Figure 2.

The superposition and alignment of the training data set using molecule 2 as a template

IJQSPR.2021010102.f02

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