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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Pharmacology of Infectious Diseases
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1457012

A cheminformatics and network pharmacology approach to elucidate the mechanism of action of Mycobacterium tuberculosis γ-carbonic anhydrase inhibitors

Provisionally accepted
Ratul Bhowmik Ratul Bhowmik 1Ajay Manaithiya Ajay Manaithiya 1Kunal Bhattacharya Kunal Bhattacharya 2Sagar Singh Shyamal Sagar Singh Shyamal 3Rajarshi Ray Rajarshi Ray 1Claudiu Supuran Claudiu Supuran 4Fabrizio Carta Fabrizio Carta 4Seppo Parkkila Seppo Parkkila 1Ashok Aspatwar Ashok Aspatwar 1*
  • 1 Tampere University, Tampere, Finland
  • 2 Royal Global University, Guwahati, Assam, India
  • 3 Department of Pharmaceutics, Indian institute of Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
  • 4 Department of Neuroscience, Psychology, Drugs and Child Health Area, School of Psychology, University of Florence, Florence, Tuscany, Italy

The final, formatted version of the article will be published soon.

    Background: Mycobacterium tuberculosis (Mtb) carbonic anhydrases (CAs) are critical enzymes that regulate pH by converting CO2 to HCO3 -, essential for Mtb's survival in acidic environments. Inhibiting γ-CAs presents a potential target for novel antituberculosis drugs with unique mechanisms of action.Objective: This study aimed to explore the biological connections underlying Mtb pathogenesis and investigate the mechanistic actions of antituberculosis compounds targeting the Cas9 protein.We employed homology modeling and virtual screening to identify compounds with high binding affinities for Cas9 protein. This study used the homology modeling approach employing high-quality AlphaFold DB models for γ-CA. Furthermore, the systems biology approach was used for analyzing the mechanistic modeling of compounds, integrating data on genes, pathways, phenotypes, and molecular descriptors. Single-cell RNA sequencing was also conducted to profile gene expression.Results: Three compounds, F10921405, F08060425, and F14437079, potentially binding to Cas9 protein, have been identified. F10921405 and F08060425 showed significant overlap in their effects on pathways related to the immune response, while F14437079 displayed distinct mechanistic pathways. Expression profiling revealed high levels of genes such as PDE4D, ROCK2, ITK, MAPK10, and SYK in response to F1092-1405 and F0806-0425, and MMP2 and CALCRL in response to F1443-7079. These genes, which play a role in immune modulation and lung tissue integrity, are essential to fight against Mtb.The molecular relationship and pathways linked to the mentioned compounds give the study a holistic perspective of targeting Mtb, which is essential in designing specific therapeutic approaches. Subsequent research will involve experimental validation to demonstrate the efficacy of the promising candidates in Mtb infections.

    Keywords: Mycobacterium tuberculosis, γ-CAs, Virtual Screening, system biology, inflammatory responses

    Received: 29 Jun 2024; Accepted: 15 Aug 2024.

    Copyright: © 2024 Bhowmik, Manaithiya, Bhattacharya, Shyamal, Ray, Supuran, Carta, Parkkila and Aspatwar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ashok Aspatwar, Tampere University, Tampere, Finland

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.