Ghoneim Mohammed M, Al-Serwi Rasha Hamed, El-Sherbiny Mohamed, El-Ghaly El-Sayed M, Hamad Amal E, Abdelgawad Mohamed A, Ragab Ehab A, Bukhari Sarah I, Bukhari Khulud, Elokely Khaled, Nael Manal A
Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Riyadh 11597, Saudi Arabia.
Curr Issues Mol Biol. 2022 Sep 27;44(10):4490-4499. doi: 10.3390/cimb44100307.
In the search for a new anti-MRSA lead compound, emodin was identified as a good lead against methicillin-resistant (MRSA). Emodin serves as a new scaffold to design novel and effective anti-MRSA agents. Because rational drug discovery is limited by the knowledge of the drug target, α-hemolysin of was used in this study because it has an essential role in infections and because emodin shares structural features with compounds that target this enzyme. In order to explore emodin's interactions with α-hemolysin, all possible ligand binding pockets were identified and investigated. Two ligand pockets were detected based on bound ligands and other reports. The third pocket was identified as a cryptic site after molecular dynamics (MD) simulations. MD simulations were conducted for emodin in each pocket to identify the most plausible ligand site and to aid in the design of potent anti-MRSA agents. Binding of emodin to site 1 was most stable (RMSD changes within 1 Å), while in site 2, the binding pose of emodin fluctuated, and it left after 20 ns. In site 3, it was stable during the first 50 ns, and then it started to move out of the binding site. Site 1 is a possible ligand binding pocket, and this study sheds more light on interaction types, binding mode, and key amino acids involved in ligand binding essential for better lead design. Emodin showed an IC value of 6.3 μg/mL, while 1, 6, and 8 triacetyl emodin showed no activity against MRSA. A molecular modeling study was pursued to better understand effective binding requirements for a lead.
在寻找新型抗耐甲氧西林金黄色葡萄球菌（MRSA）先导化合物的过程中，大黄素被确定为一种对抗耐甲氧西林金黄色葡萄球菌的良好先导物。大黄素可作为设计新型有效抗MRSA药物的新支架。由于合理的药物发现受到药物靶点知识的限制，本研究使用了α-溶血素，因为它在感染中起关键作用，且大黄素与靶向该酶的化合物具有共同的结构特征。为了探究大黄素与α-溶血素的相互作用，确定并研究了所有可能的配体结合口袋。基于结合的配体和其他报告检测到两个配体口袋。通过分子动力学（MD）模拟后，第三个口袋被确定为一个隐蔽位点。对大黄素在每个口袋中进行MD模拟，以确定最合理的配体位点，并辅助设计强效抗MRSA药物。大黄素与位点1的结合最稳定（均方根偏差变化在1 Å以内），而在位点2，大黄素的结合构象波动，在20 ns后离开。在位点3，它在前50 ns内稳定，然后开始移出结合位点。位点1是一个可能的配体结合口袋，本研究为更好的先导物设计所必需的相互作用类型、结合模式以及参与配体结合的关键氨基酸提供了更多信息。大黄素的IC值为6.3 μg/mL，而1, 6, 8-三乙酰大黄素对MRSA无活性。开展了一项分子建模研究，以更好地了解先导物的有效结合要求。
