Computer-aided identification of human carbonic anhydrase isoenzyme VII inhibitors as potential antiepileptic agents

• Published in: Journal of biomolecular structure & dynamics 2022-06, Vol.40 (11), p.4850-4865
• Main Authors: Kumar, Avinash, Agarwal, Paridhi, Rathi, Ekta, Kini, Suvarna G.
• Format: Article
• Language: English
• Subjects: CADD; docking; epilepsy; pharmacophore modelling; QSAR
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2020.1862706

Human carbonic anhydrase (hCA) belongs to a superfamily of metalloenzymes that reversibly catalyse the hydration of carbon dioxide to give bicarbonate (HCO 3 − ) and proton (H + ). As HCO 3 − ions play an important role in neuronal signalling hence, hCA enzymes are an attractive target for antiepileptic drugs. Out of all the isoforms, hCA VII is predominantly expressed in the brain cortex and hippocampus region, which are the most affected area during seizure activity. Hence, we have identified some hCA VII inhibitors employing computational tools like atom-based 3D quantitative structure-activity relationship (QSAR), auto-QSAR, pharmacophore-based virtual screening, molecular docking, and molecular dynamics (MD) simulations. Atom-based 3D QSAR modelling outperformed auto-QSAR with an R 2 and Q 2 value of 0.9634 and 0.9646, respectively. A four-feature pharmacophore model (AADR_1) was developed and a focussed library of around 3,00,000 compounds was screened. Compounds with a phase screen score >2.40 were selected for docking studies. The activity of the selected hits was predicted employing the developed 3D QSAR model. Finally, three compounds were taken up for the MD simulation studies which also suggest that the identified hits might form a stable complex with hCA VII enzyme. A comparative docking study was also done with other hCA isoforms like I, II, IV, IX, and XII to examine the selectivity of the identified hits towards hCA VII. Based on these studies, three hits have been identified as potential hCA VII inhibitor which is drug-like molecules. Further, in vitro studies are required to develop leads from these identified hits. Communicated by Ramaswamy H. Sarma