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

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 (IC50exp). Active bound conformation of the CSAM1-14 assessment led to linear correlation between computed enthalpy of hCA II-CSAMx complexes formation in gas phase (ΔΔHMM) with the IC50exp. 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 (ΔΔGcom) and IC50exp. 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: pIC50exp = -0.068×ΔΔHMM + 7.722, R2 = 0.82; GFE QSAR model: pIC50exp = - 0.061× ΔΔGcom + 7.647, R2 = 0.92 and PH4 model: pIC50exp = 1.095×pIC50pre – 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 Mw ≤ 500 g/mol). The three-point PH4-based screening identified 81 novel CSAMs with predicted IC50pre reaching 78-times better than CSAM1 potency (IC50exp = 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.