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 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 C. 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.

中文翻译：

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2-(4-氟苯基)-6-甲基-3-(吡啶-4-基)吡唑并[1,5-a]吡啶的结构类似物通过蛋白质配体结合和动力学靶向白色念珠菌非必需应激激酶Yck2分析


耐药真菌感染的增加引起了重大的公共卫生问题，因此需要开发新的抗真菌疗法。我们旨在通过针对白色念珠菌的酵母酪蛋白激酶进行抗真菌药物开发来应对这一挑战。该化合物库包含 589 个与之前鉴定的激酶抑制剂 GW461484A 相似的化学结构。通过虚拟筛选，根据结合能选择了 PubChem ID 为 102583821、12982634、102487860 和 86260205 的四种化合物。疏水键和范德华相互作用稳定了对接的复合物。全面的相互作用研究和 200 纳秒分子动力学模拟表明，这些分子可以与目标保持稳定的相互作用，令人满意的 RMSD 和 RMSF 值证明了这一点。这些配合物基于 Rg-RMSD 的自由能图谱表明，由于存在具有全局最小值的构象异构体，因此具有热力学稳定性。这些有希望的发现凸显了开发针对白色念珠菌 Yck2 的新型抗真菌疗法的潜力。需要进一步的实验验证来评估这些化合物作为抗真菌剂的功效。这项研究为对抗抗真菌耐药性迈出了重要一步，并为药物发现开辟了新途径。