Rabaan Ali A, Alfouzan Wadha A, Garout Mohammed, Halwani Muhammad A, Alotaibi Nouf, Alfaresi Mubarak, Al Kaabi Nawal A, Almansour Zainab H, Bueid Ahmed S, Yousuf Amjad A, Eid Hamza M A, Alissa Mohammed
Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
J Biomol Struct Dyn. 2024 Apr 18:1-17. doi: 10.1080/07391102.2024.2332507.
In response to the escalating threat of drug-resistant fungi to human health, there is an urgent need for innovative strategies. Our focus is on addressing this challenge by exploring a previously untapped target, yeast casein kinase (Yck2), as a potential space for antifungal development. To identify promising antifungal candidates, we conducted a thorough screening of the diverse-lib drug-like molecule library, comprising 99,288 molecules. Five notable drug-like compounds with diverse-lib IDs 24334243, 24342416, 17516746, 17407455, and 24360740 were selected based on their binding energy scores surpassing 11 Kcal/mol. Our investigation delved into the interaction studies and dynamic stability of these compounds. Remarkably, all selected molecules demonstrated acceptable RMSD values during the 200 ns simulation, indicating their stable nature. Further analysis through Principal Component Analysis (PCA)-based Free Energy Landscape (FEL) revealed minimal energy transitions for most compounds, signifying dynamic stability. Notably, the two compounds exhibited slightly different behaviour in terms of energy transitions. These findings mark a significant breakthrough in the realm of antifungal drugs against by targeting the Yck2 protein. However, it is crucial to note that additional experimental validation is imperative to assess the efficacy of these molecules as potential antifungal candidates. This study serves as a promising starting point for further exploration and development in the quest for effective antifungal solutions.
鉴于耐药真菌对人类健康的威胁不断升级，迫切需要创新策略。我们的重点是通过探索一个以前未被开发的靶点——酵母酪蛋白激酶（Yck2），作为抗真菌药物开发的潜在领域，来应对这一挑战。为了确定有前景的抗真菌候选物，我们对包含99288个分子的多样化类药物分子库进行了全面筛选。基于其结合能得分超过11千卡/摩尔，选择了五个具有多样化类药物标识24334243、24342416、17516746、17407455和24360740的显著类药物化合物。我们的研究深入探讨了这些化合物的相互作用研究和动态稳定性。值得注意的是，在200纳秒的模拟过程中，所有选定的分子都表现出可接受的均方根偏差（RMSD）值，表明它们的稳定性。通过基于主成分分析（PCA）的自由能景观（FEL）的进一步分析表明，大多数化合物的能量转换最小，这意味着动态稳定性。值得注意的是，这两种化合物在能量转换方面表现出略有不同的行为。这些发现标志着通过靶向Yck2蛋白对抗真菌药物领域的重大突破。然而，必须注意的是，需要额外的实验验证来评估这些分子作为潜在抗真菌候选物的功效。这项研究为寻求有效的抗真菌解决方案的进一步探索和开发提供了一个有希望的起点。
