Pitaloka Dian Ayu Eka, Arfan Arfan, Khairunnisa Shafa Fitri, Megantara Sandra
Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, 45363, Indonesia; Center of Excellence in Higher Education for Pharmaceutical Care Innovation, Universitas Padjadjaran, Sumedang, 45363, Indonesia.
Department of Medicinal Chemistry, Faculty of Pharmacy, Universitas Halu Oleo, Kendari, Indonesia.
Comput Biol Med. 2025 Mar;186:109677. doi: 10.1016/j.compbiomed.2025.109677. Epub 2025 Jan 21.
A higher death rate is associated with multiple factors, including medication resistance and co-infection with the human immunodeficiency virus (HIV). This shows the need to obtain new and effective drug candidates in improving tuberculosis (TB) treatment. In addition, the phosphatidylinositol mannosyltransferase (PimA) enzyme starts the production of phosphatidyl-myo-inositol. PimA has been identified as a key enzyme and an important area for further research in the development of anti-TB drugs. Previous research investigated various applications including marine resources driven by a deeper understanding of the distinctive features of the ecosystem and the diverse array of organisms. Therefore, this research aims to investigate the potential of Indonesian marine compounds as inhibitors of PimA, with a focus on binding energy, interaction modes, and stability using docking and molecular dynamics (MD) investigation methodologies. The results show that a total of 84 Indonesian marine compounds are effectively docked to the PimA to obtain compounds 21, 27, and 33 for further investigation. Based on the MD analysis, compound 27 (desulfohaplosamate) is the most promising candidate among the new MTB-PimA inhibitors. Compounds bind to PimA, as shown by a strong affinity of -30.09 kJ/mol, and form hydrogen bonds with the key amino acid residue Gly16. Furthermore, a stable complex is formed to easily analyze the antibacterial agents targeting MTB in the future.
较高的死亡率与多种因素相关，包括耐药性以及与人类免疫缺陷病毒（HIV）的合并感染。这表明在改善结核病（TB）治疗方面需要获得新的有效候选药物。此外，磷脂酰肌醇甘露糖基转移酶（PimA）启动磷脂酰 - 肌醇的生成。PimA已被确定为抗结核药物开发中的关键酶和一个重要的进一步研究领域。以往的研究调查了各种应用，包括基于对生态系统独特特征和多样生物种类的更深入理解而开发的海洋资源。因此，本研究旨在利用对接和分子动力学（MD）研究方法，研究印度尼西亚海洋化合物作为PimA抑制剂的潜力，重点关注结合能、相互作用模式和稳定性。结果表明，共有84种印度尼西亚海洋化合物有效地对接至PimA，从而获得化合物21、27和33以进行进一步研究。基于MD分析，化合物27（去磺基哈普洛沙胺）是新型结核分枝杆菌 - PimA抑制剂中最有前景的候选物。化合物与PimA结合，其亲和力为 - 30.09 kJ/mol，显示出较强的亲和力，并与关键氨基酸残基Gly16形成氢键。此外，形成了稳定的复合物，便于未来分析针对结核分枝杆菌的抗菌剂。
