Journal of Pharmaceutical Research International

Virtual Design of Novel Coumarinyl-Substituted Sulfonamide Inhibitors of Carbonic Anhydrase II as Potential Drugs against Glaucoma

Eric Ziki

Laboratoire of Cristallographie et Physique Moléculaire, University of Cocody, (Now Félix Houphouët-Boigny), Abidjan, Côte d’Ivoire.

Ludovic Akonan

Laboratoire de Physique Fondamentale et Appliquée (LPFA), University of Abobo Adjamé (now Nangui Abrogoua), Abidjan, Côte d’Ivoire.

Koffi Charles Kouman

Laboratoire de Physique Fondamentale et Appliquée (LPFA), University of Abobo Adjamé (now Nangui Abrogoua), Abidjan, Côte d’Ivoire.

Brice Dali

Laboratoire of Cristallographie et Physique Moléculaire, University of Cocody, (Now Félix Houphouët-Boigny), Abidjan, Côte d’Ivoire and Laboratoire de Physique Fondamentale et Appliquée (LPFA), University of Abobo Adjamé (now Nangui Abrogoua), Abidjan, Côte d’Ivoire.

Eugene Megnassan *

Laboratoire of Cristallographie et Physique Moléculaire, University of Cocody, (Now Félix Houphouët-Boigny), Abidjan, Côte d’Ivoire and Laboratoire de Physique Fondamentale et Appliquée (LPFA), University of Abobo Adjamé (now Nangui Abrogoua), Abidjan, Côte d’Ivoire and Laboratoire de Chimie Organique Structurale et Théorique, University of Cocody (now Felix Houphouët-Boigny), Abidjan, Côte d’Ivoire and International Centre for Theoretical Physics, ICTP-UNESCO, Strada Costiera 11, Trieste I-34151, Italy and International Centre for Applied Research and Sustainable Technology, Bratislava SK-84104, Slovakia.

Rita Kakou-Yao

Laboratoire of Cristallographie et Physique Moléculaire, University of Cocody, (Now Félix Houphouët-Boigny), Abidjan, Côte d’Ivoire.

Abodou Jules Tenon

Laboratoire of Cristallographie et Physique Moléculaire, University of Cocody, (Now Félix Houphouët-Boigny), Abidjan, Côte d’Ivoire.

Vladimir Frecer

International Centre for Applied Research and Sustainable Technology, Bratislava SK-84104, Slovakia and Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava SK-83232, Slovakia.

Stanislav Miertus

International Centre for Applied Research and Sustainable Technology, Bratislava SK-84104, Slovakia and Department of Biotechnologies, Faculty of Natural Sciences, University of SS. Cyril and Methodius, Trnava SK-91701, Slovakia.

*Author to whom correspondence should be addressed.

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Abstract

Background: We have carried out virtual design of coumarinyl-substituted sulfonamides (CSAM) analogs as inhibitors of human carbonic anhydrase II (hCA II) endowed with favorable predicted pharmacokinetic profiles and potential therapeutic effects against glaucoma.

Methods: modifying in situ the x-ray structure of 2-(7-methoxy-2-oxo-2H-chromen-4-yl)-N-(4-sulfamoyl-phenyl)-acetamide (CSAM0)-hCA II complex (PDB entry 3ML2), permitted 3D models of hCA II-CSAMx complexes preparation for a TS of 14 CSAMs the experimental activities of which are available in the literature (IC₅₀^exp). Active bound conformation of the CSAM1-14 assessment led to linear correlation between computed enthalpy of hCA II-CSAMx complexes formation in gas phase (ΔΔH_MM) with the IC₅₀^exp. Moreover, considering the solvation and ligand loss of entropy upon binding led to a superior QSAR model where a better linear correlation is established between calculated GFE (ΔΔG_com) and IC₅₀^exp. The successive 3D-pharmacophore (PH4) built from CSAMs active conformations helped to virtually screen CSAM populating a sulfonamides scaffolds virtual combinatorial library (VCL), focused by Lipinski’s rule-of-five to reach novel CSAMs.

Results: Enthalpy QSAR model: pIC₅₀^exp = -0.068×ΔΔH_MM + 7.722, R² = 0.82; GFE QSAR model: pIC₅₀^exp = - 0.061× ΔΔG_com + 7.647, R² = 0.92 and PH4 model: pIC₅₀^exp = 1.095×pIC₅₀^pre – 0.680, R² = 0.87. The VCL of more than 1,500,625 CSAMs was lowered to 865,670 drug likely compounds by the Lipinski’s rule (except the restriction M_w ≤ 500 g/mol). The three-point PH4-based screening identified 81 novel CSAMs with predicted IC₅₀^pre reaching 78-times better than CSAM1 potency (IC₅₀^exp = 23 nM). Computed pharmacokinetic profile of the new candidates showed enhanced cell membrane permeability and high human oral absorption compared to current anti-glaucoma agents.

Conclusions: Combination of QSAR models of the CSAMs’ affinity to the hCA II, pharmacophore model, and ADME profile guided to the sulfonamides inhibitors identification and helped to in silico screen VCL sulfonamides scaffold bearing analogs and allowed emerging of novel more potent compounds with predicted IC₅₀ and favorable pharmacokinetic profiles.

Keywords: Coumarin, glaucoma, sulfonamide, carbonic anhy-drase II, molecular modeling, QSAR models, pharmacophore, virtual combinatorial library, in silico screening, ADME properties prediction

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