ICMR-Regional Medical Research Centre (Dept. of Health Research, Ministry of Health & Family Welfare, Govt. of India), Chandrasekharpur, Odisha, India.
KIIT School of Biotechnology, Patia, Bhubaneswar, Odisha, India.
J Biomol Struct Dyn. 2023 Mar;41(4):1267-1280. doi: 10.1080/07391102.2021.2019125. Epub 2021 Dec 28.
Amid the rise of multi-drug resistance among bacterial pathogens, the drying of the development pipeline of new antibiotics is worrisome. In search of new effective alternatives, phytocompounds can be considered a good one because of their immense antimicrobial property, low toxicity and huge structural diversity. In the present study, 200 phytocompounds were targeted against two Metallo β-lactamase (MBL) enzymes (NDM-1 and VIM-1) through molecular docking and meropenem was used as a reference drug. The phytocompounds with docking score ≤-8.0 kcal/mol were screened for their pharmacokinetic properties. The three best selected phytocompounds are Coriandrinonediol, Oleanderolide and Uzarigenin. Molecular docking helps to understand binding affinity. The selected phytocompounds showed better result than meropenem. Molecular interaction study reveals their competitive mechanism of inhibition against the target proteins. Coriandrinonediol has docking score -8.3 kcal/mol (NDM-1) and -8.9 kcal/mol (VIM-1), and oleanderolide has docking score -8.2 kcal/mol (NDM-1) and -9.3 kcal/mol (VIM-1). Uzarigenin has the highest binding affinity (-10.4 kcal/mol) among the three against VIM-1 and the lowest binding affinity (-8.1 kcal/mol) against NDM-1. Molecular dynamic (MD) simulation study also supports the stability and flexibility of the above phytocompounds during the MD run. Among the abovementioned three phytocompounds, oleanderolide has given the best result against both target proteins. These phytocompounds are first time reported as MBL inhibitors and their promising in silico results encourage to promote them for further investigation for in vitro and in vivo clinical trials.Communicated by Ramaswamy H. Sarma.
在细菌病原体对抗生素耐药性日益增强的情况下，新抗生素研发管道的枯竭令人担忧。为了寻找新的有效替代品，植物化合物因其巨大的抗菌特性、低毒性和巨大的结构多样性，可以被认为是一个很好的选择。在本研究中，通过分子对接，针对两种金属β-内酰胺酶（MBL）酶（NDM-1 和 VIM-1）靶向了 200 种植物化合物，并用美罗培南作为参考药物。对接得分≤-8.0 kcal/mol 的植物化合物被筛选出其药代动力学性质。三种最佳选择的植物化合物是芫荽酮二醇、夹竹桃苷和乌索苷。分子对接有助于理解结合亲和力。所选植物化合物的结果优于美罗培南。分子相互作用研究揭示了它们抑制靶蛋白的竞争机制。芫荽酮二醇对 NDM-1 的对接得分为-8.3 kcal/mol，对 VIM-1 的对接得分为-8.9 kcal/mol；夹竹桃苷对 NDM-1 的对接得分为-8.2 kcal/mol，对 VIM-1 的对接得分为-9.3 kcal/mol。乌索苷对 VIM-1 的结合亲和力最高（-10.4 kcal/mol），对 NDM-1 的结合亲和力最低（-8.1 kcal/mol）。分子动力学（MD）模拟研究也支持了上述三种植物化合物在 MD 运行过程中的稳定性和灵活性。在上述三种植物化合物中，夹竹桃苷对两种靶蛋白的效果最好。这些植物化合物是首次被报道为 MBL 抑制剂，它们有前途的计算机模拟结果鼓励进一步研究它们用于体外和体内临床试验。由 Ramaswamy H. Sarma 传达。
