Singh Vishakha, Dhankhar Poonam, Dalal Vikram, Tomar Shailly, Kumar Pravindra
Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, 247667, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, 247667, India.
J Mol Graph Model. 2022 Nov;116:108262. doi: 10.1016/j.jmgm.2022.108262. Epub 2022 Jun 30.
Klebsiella pneumonia is known to cause several nosocomial infections in immunocompromised patients. It has developed resistance against a broad range of presently available antibiotics, resulting in high mortality rates in patients and declared an urgent threat. Therefore, exploration of possible novel drug targets against this opportunistic bacteria needs to be undertaken. In the present study, we performed an extensive in-silico analysis for functional and structural annotation and characterized HP CP995_08280 from K. pneumonia as a drug target and aimed to identify potent drug candidates. The functional and structural studies using several bioinformatics tools and databases predicted that HP CP995_08280 is a cytosolic protein that belongs to the β-lactamase family and shares structural similarity with FmtA protein from Staphylococcus aureus (PDB ID: 5ZH8). The structure of HP CP995_08280 was successfully modeled followed by structure-based virtual screening, docking, molecular dynamics, and Molecular mechanic/Poisson-Boltzmann surface area (MMPBSA) were performed to identify the potential compounds. We have found five potent antibacterial molecules, namely BDD 24083171, BDD 24085737, BDE 25098678, BDE 33638819, and BDE 33672484, which exhibited high binding affinity (>-7.5 kcal/mol) and were stabilized by hydrogen bonding and hydrophobic interactions with active site residues (Ser42, Lys45, Tyr126, and Asp128) of protein. Molecular dynamics and MMPBSA revealed that HP CP995_08280 - ligand(s) complexes were less dynamic and more stable than native HP CP995_08280. Hence, the present study may serve as a potential lead for developing inhibitors against drug-resistant Klebsiella pneumonia.
已知肺炎克雷伯菌会在免疫功能低下的患者中引发多种医院感染。它已对目前广泛使用的多种抗生素产生耐药性，导致患者死亡率很高，并被宣布为紧急威胁。因此，需要探索针对这种机会致病菌的可能的新型药物靶点。在本研究中，我们进行了广泛的计算机模拟分析，以进行功能和结构注释，并将肺炎克雷伯菌的HP CP995_08280鉴定为药物靶点，旨在识别有效的候选药物。使用多种生物信息学工具和数据库进行的功能和结构研究预测，HP CP995_08280是一种胞质蛋白，属于β-内酰胺酶家族，与金黄色葡萄球菌的FmtA蛋白（PDB ID：5ZH8）具有结构相似性。成功构建了HP CP995_08280的结构模型，随后进行了基于结构的虚拟筛选、对接、分子动力学和分子力学/泊松-玻尔兹曼表面积（MMPBSA）分析，以鉴定潜在化合物。我们发现了五种有效的抗菌分子，即BDD 24083171、BDD 24085737、BDE 25098678、BDE 33638819和BDE 33672484，它们表现出高结合亲和力（>-7.5千卡/摩尔），并通过与蛋白质活性位点残基（Ser42、Lys45、Tyr126和Asp128）的氢键和疏水相互作用而稳定。分子动力学和MMPBSA分析表明，HP CP995_08280-配体复合物比天然HP CP995_08280的动态性更低、更稳定。因此，本研究可能为开发针对耐药性肺炎克雷伯菌的抑制剂提供潜在线索。
