Centre for Drug Design Discovery and Development (C4D), SRM University, Sonepat, Haryana, India.
CCS National Institute of Animal Health, Baghpat, Uttar Pradesh, India.
J Biomol Struct Dyn. 2023 Jul;41(11):5117-5126. doi: 10.1080/07391102.2022.2080113. Epub 2022 Jun 2.
The present study is conducted to find the solution of rising antimicrobial resistance (AMR) in which is a pathogen responsible for fatal systemic infections in human and animals. The enzyme dihydrofolate reductase (DHFR) is found in all organisms. In this study DHFR of (ec-DHFR) and human DHFR (h-DHFR) is targeted by novel chemical entities (NCE) from the Pathogen box of Medicines for Malaria Venture, Switzerland (MMV) using molecular modelling. The studies were further validated by assays. The virtual screening of 400 MMV compounds was conducted using PyRx standard tool followed by manual docking of selected compounds by Autodock vina and Ligplot program. The studies showed good binding energy and strong hydrogen bond in docking of MMV675968 with ec-DHFR and no hydrogen bond with h-DHFR. This was further validated by the Molecular dynamic studies that revealed high binding free energy in ec-DHFR and assays that produced good synergy in combination study of MMV675968 with last line (meropenem) and last resort (colistin) antibiotics. The extensive MD simulation and energetic analysis thus concludes that MMV675968 targets ec-DHFR. The combination studies were conducted with MMV675968 and FDA approved drugs against a panel of multidrug resistant isolates. The synergistic results obtained in combination studies concluded that data is consistent with data and that MMV675968 is a potential lead for future process of antimicrobial drug development against the multidrug resistance .Communicated by Ramaswamy H. Sarma.
本研究旨在寻找解决抗菌药物耐药性（AMR）上升的方法，这种耐药性是导致人类和动物致命全身感染的病原体。二氢叶酸还原酶（DHFR）存在于所有生物体中。在这项研究中，使用分子建模方法，针对来自瑞士医药疟疾 Venture（MMV）病原体盒的新型化学实体（NCE），对 （ec-DHFR）和人 DHFR（h-DHFR）的 DHFR 进行了研究。进一步通过酶抑制实验验证了这些研究。使用 PyRx 标准工具对 400 种 MMV 化合物进行了虚拟筛选，然后通过 Autodock vina 和 Ligplot 程序手动对接选定的化合物。研究表明，在 ec-DHFR 与 MMV675968 的对接中，结合能良好，氢键较强，而与 h-DHFR 没有氢键。分子动力学研究进一步验证了这一点，该研究表明 ec-DHFR 具有高结合自由能，酶抑制实验表明 MMV675968 与最后一线（美罗培南）和最后手段（多粘菌素）抗生素联合使用具有良好的协同作用。广泛的 MD 模拟和能量分析得出结论，MMV675968 靶向 ec-DHFR。与 MMV675968 以及 FDA 批准的药物对一组多药耐药 分离株进行了联合研究。联合研究中获得的协同结果表明，这些数据与 数据一致，并且 MMV675968 是针对多药耐药 的未来抗菌药物开发的潜在先导化合物。由 Ramaswamy H. Sarma 传达。
