Department of Biotechnology, National Institute of Technology (NIT), Raipur, India.
Department of Biotechnology, National Institute of Technology (NIT), Raipur, India.
Microb Pathog. 2018 Jan;114:8-16. doi: 10.1016/j.micpath.2017.11.009. Epub 2017 Nov 11.
Salmonella typhimurium is the causative agent of severe human infections and mortality throughout the world. Pacing advent of new resistance mechanisms in this microorganism exists, rendering treatment of infectious disease difficult. Ciprofloxacin is no longer considered the first choice of antimicrobial agent due to the emergence of resistance. Therefore, the need for scenario is to find out novel drug target and its potential inhibitor to fight against this pathogen. The present study was undertaken to find out a novel drug target and its inhibitor for improving the current therapeutic methods for treating Salmonella infections. It is found that l-asparaginase is exploited by the pathogen for its survival benefit. Therefore, it could be targeted to fight against lethality caused by Salmonella infections. In the present in silico study, the 3-D structure of the enzyme l-asparaginase was modelled by using homology modeling technique. Thereafter, molecular docking studies and ADMET prediction to assess pharmacokinetic profiles of test ligands (eugenol and its derivative) was performed. The results show that eugenol and its derivative are capable of inhibiting the Salmonella virulent protein l-asparaginase. There were 18 ligands including ciprofloxacin (used as reference) were docked. The lowest binding energy was observed with eugenol derivative 8 i.e -5.836 kcal/mol while for ciprofloxacin was -4.661 kcal/mol. The docking of the eugenol derivative 8 with l-asparaginase revealed a strong interaction between them with two hydrogen bonds. Thr 35 and Asp 116 residues are actively participating in this interaction. The result of ADMET profiling suggests the potency of eugenol and its derivatives against Salmonellal-asparaginase-II as a compelling drug candidate. These findings provide useful information on the biological role, structure-based drug design and potent inhibitor of l-asparaginase for the development of effective therapeutic molecule against Salmonella infection.
鼠伤寒沙门氏菌是导致全世界严重人类感染和死亡的病原体。由于这种微生物中新的耐药机制的出现，使得传染病的治疗变得困难。由于耐药性的出现，环丙沙星不再被认为是首选的抗菌药物。因此，需要找到新的药物靶点及其潜在抑制剂来对抗这种病原体。本研究旨在寻找一种新的药物靶点及其抑制剂，以改善目前治疗沙门氏菌感染的方法。研究发现，病原体利用 l-天冬酰胺酶来获得生存优势。因此，它可以作为靶点来对抗由沙门氏菌感染引起的致死性。在本计算机模拟研究中，使用同源建模技术对酶 l-天冬酰胺酶的 3-D 结构进行建模。随后，进行分子对接研究和 ADMET 预测，以评估测试配体（丁香酚及其衍生物）的药代动力学特征。结果表明，丁香酚及其衍生物能够抑制沙门氏菌毒力蛋白 l-天冬酰胺酶。共对接了 18 个配体，包括环丙沙星（用作参考）。丁香酚衍生物 8 的最低结合能为-5.836 kcal/mol，而环丙沙星的结合能为-4.661 kcal/mol。丁香酚衍生物 8 与 l-天冬酰胺酶的对接揭示了它们之间的强相互作用，有两个氢键。 Thr 35 和 Asp 116 残基积极参与了这种相互作用。ADMET 分析结果表明，丁香酚及其衍生物对 Salmonellal-asparaginase-II 的活性，使其成为一种有前途的药物候选物。这些发现为 l-天冬酰胺酶的生物学作用、基于结构的药物设计和潜在抑制剂提供了有用的信息，为开发针对沙门氏菌感染的有效治疗分子提供了依据。
