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ORIGINAL RESEARCH article

Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 12 - 2024 | doi: 10.3389/fchem.2024.1430157

Structural Analogs of 2-(4-fluorophenyl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridine for Targeting Candida albicans Non-essential Stress Kinase Yck2 through Protein-Ligand Binding and Dynamics Analysis

Provisionally accepted
Ahmed M. Hassan Ahmed M. Hassan 1Aiah Khateb Aiah Khateb 1,2Safaa A. Turkistani Safaa A. Turkistani 1,3Meshari M. Alhamdan Meshari M. Alhamdan 1,4Raed M. Garout Raed M. Garout 1Vivek D. Dwivedi Vivek D. Dwivedi 5,6*Esam Ibraheem Azhar Esam Ibraheem Azhar 1*
  • 1 King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 2 Taibah University, Medina, Al Madinah, Saudi Arabia
  • 3 Fakeeh College of Medical Sciences, Jeddah, Saudi Arabia
  • 4 Faculty of Medicine, King Abdulaziz University, Jeddah, Makkah, Saudi Arabia
  • 5 Center for Global Health Research, Saveetha Medical College & Hospital, Chennai, Tamil Nadu, India
  • 6 Bioinformatics Research Division, Quanta Calculus, Greater Noida, India

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

    The rise in drug-resistant fungal infections poses a significant public health concern, necessitating the development of new antifungal therapies. We aimed to address this challenge by targeting a yeast casein kinase of Candida albicans for antifungal drug development. The compound library contained 589 chemical structures similar to the previously identified kinase inhibitor GW461484A. Through virtual screening, four compounds with the PubChem IDs 102583821, 12982634, 102487860, and 86260205 were selected based on their binding energies. Hydrophobic bonds and van der Waals interactions stabilised the docked complexes. Comprehensive interaction studies and a 200nanosecond molecular dynamics simulation suggested that these molecules can maintain stable interactions with the target, as evidenced by satisfactory RMSD and RMSF values. The Rg-RMSDbased Free Energy Landscape of these complexes indicated thermodynamic stability due to the presence of conformers with global minima. These promising findings highlight the potential for developing novel antifungal therapies targeting Yck2 in Candida albicans. Further experimental validation is required to assess the efficacy of these compounds as antifungal agents. This research provides a significant step towards combating antifungal resistance and opens up a new avenue for drug discovery.

    Keywords: Yeast casein kinase (Yck2), C. albicans, Free energy landscape, Molecular dynamic simulation, High Throughput Virtual Screening (HTVS)

    Received: 14 May 2024; Accepted: 05 Jul 2024.

    Copyright: © 2024 Hassan, Khateb, Turkistani, Alhamdan, Garout, Dwivedi and Azhar. 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:
    Vivek D. Dwivedi, Center for Global Health Research, Saveetha Medical College & Hospital, Chennai, Tamil Nadu, India
    Esam Ibraheem Azhar, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, 22252, Makkah, Saudi Arabia

    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.