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

• Published in: Frontiers in chemistry 2024-08, Vol.12, p.1430157
• Main Authors: Hassan, Ahmed M, Khateb, Aiah M, Turkistani, Safaa A, Alhamdan, Meshari M, Garout, Raed M, Dwivedi, Vivek Dhar, Azhar, Esam I
• Format: Article
• Language: English
• Subjects: C. albicans; Chemistry; free energy landscape; high throughput virtual screening (HTVS); molecular dynamic simulation; yeast casein kinase (Yck2)
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2024.1430157

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 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 200-nanosecond molecular dynamics simulation suggested that these molecules can maintain stable interactions with the target, as evidenced by satisfactory RMSD and RMSF values. The Rg-RMSD-based 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 . 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.