Nanobiotechnology Research Group, Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
DSI/Mintek Nanotechnology Innovation Centre (NIC), Biolabels Research Node, Department of Biotechnology, University of the Western Cape, Private Bag X17, Bellville, Cape Town 7535, South Africa.
Biomed Res Int. 2023 Oct 12;2023:8022356. doi: 10.1155/2023/8022356. eCollection 2023.
The evolution of antibiotic-resistant carbapenemase has negatively impacted the management of critical healthcare-associated infections. carbapenemase-2- (KPC-2-) expressing bacteria have developed resistance to conventional therapeutic options, including those used as a last resort for life-threatening diseases. In this study, species phytoconstituents were screened for their potential to inhibit KPC-2 protein using approaches. Molecular docking was used to identify strong KPC-2 protein binding phytoconstituents retrieved from the literature. The best-docked conformation of the ligands was selected based on their glide energy and binding interactions. To determine their binding free energies, these hit compounds were subjected to molecular mechanics with generalized born and surface area (MM-GBSA) in the PRIME module. Pharmacological assessments of the ligands were performed to evaluate their drug-likeness. Molecular dynamic (MD) simulations were used to analyze the conformational stability of the selected druglike compounds within the active site of the KPC-2 protein. Overall, a total of 69 phytoconstituents were compiled from the literature. Fourteen of these compounds exhibited a stronger binding affinity for the protein target than the reference drugs. Four of these top hit compounds, DB09, DB12, DB28, and DB66, revealed the highest efficacy in terms of drug-likeness properties. The MD simulation established that among the druglike compounds, DB66 attained stable conformations after 150 ns simulation in the active site of the protein. We concluded that DB66 from species could play a significant role in therapeutic efforts against KPC-2-expressing bacteria.
抗生素耐药碳青霉烯酶的进化对严重医疗相关感染的管理产生了负面影响。表达碳青霉烯酶-2（KPC-2）的细菌已经对传统的治疗选择产生了耐药性，包括那些用于危及生命的疾病的最后手段。在这项研究中，使用对接和分子力学与广义 Born 和表面积（MM-GBSA）方法筛选了 种植物成分，以研究其抑制 KPC-2 蛋白的潜力。使用对接方法从文献中确定了与 KPC-2 蛋白结合较强的植物成分。根据它们的滑行能量和结合相互作用，选择了最佳对接构象的配体。为了确定它们的结合自由能，将这些命中化合物在 PRIME 模块中的分子力学与广义 Born 和表面积（MM-GBSA）中进行了研究。对配体进行了药理学评估，以评估它们的类药性。使用分子动力学（MD）模拟分析了所选类药化合物在 KPC-2 蛋白活性部位的构象稳定性。总的来说，从文献中总共编译了 69 种植物成分。其中 14 种化合物对蛋白质靶标表现出比参考药物更强的结合亲和力。这四种顶级命中化合物 DB09、DB12、DB28 和 DB66 在类药性方面表现出最高的功效。MD 模拟表明，在所研究的类药化合物中，DB66 在蛋白质活性部位 150ns 模拟后达到稳定构象。我们得出结论， 种中的 DB66 可能在针对表达 KPC-2 的细菌的治疗努力中发挥重要作用。
