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Novel potential inhibitor discovery against tyrosyl-tRNA synthetase from Staphylococcus aureus by virtual screening, molecular dynamics, MMPBSA and QMMM simulations
Molecular Simulation ( IF 2.1 ) Pub Date : 2020-03-31 , DOI: 10.1080/08927022.2020.1726911
Chiako Farshadfar 1 , Adriano Mollica 2 , Fatemeh Rafii 3 , Akbar Noorbakhsh 1 , Mozhgan Nikzad 1 , Seyed Hamid Seyedi 1 , Fatemeh Abdi 4 , Somayeh Abbasi Verki 5 , Sako Mirzaie 6
Affiliation  

ABSTRACT The abuse and overuse of antibiotics is the main responsible for the raising antibiotic resistance among bacteria and as a consequence the of diseases severity and treatment complications. Staphylococcus aureus (S. aureus) can cause severe bloodstream infection, endocarditis and skin infection with an annual incidence of twenty-six cases per one hundred thousand people and approximately 30% of them are lethal. Among the different and diverse resistance mechanisms, S. aureus enzyme tyrosyl-tRNA synthetase (YRS) was selected as emerging target to be employed to the state of the art computer-aided drug design. At this regard, a library including the 15,387 chemicals from the Zinc database was screened by means of AutoDock Vina software. The selected hit (ZINC59675144), upon its docking binding energy and comparison with the positive control (SB284485), was subjected to molecular dynamics (MD) simulation. Following the MD, the physico-chemical parameters of the free or inhibitor-bound YRS complexes were analyzed and discussed. Our molecular modelling investigation, along with QM/MM studies, suggests that ZINC59675144 has impressive properties as a potential inhibitor of YRS, and also can be utilised as lead compound for further improvements. In addition, the ADME analysis displayed that whole physicochemical characteristics are compatible for human administration.

中文翻译:

通过虚拟筛选、分子动力学、MMPBSA 和 QMMM 模拟发现针对金黄色葡萄球菌酪氨酰-tRNA 合成酶的新型潜在抑制剂

摘要 抗生素的滥用和过度使用是导致细菌对抗生素耐药性增加、疾病严重程度和治疗并发症增加的主要原因。金黄色葡萄球菌(S. aureus)可引起严重的血流感染、心内膜炎和皮肤感染,年发病率为每 10 万人 26 例,其中约 30% 是致命的。在不同且多样的抗性机制中,金黄色葡萄球菌酶酪氨酰-tRNA 合成酶 (YRS) 被选为新兴目标,用于最先进的计算机辅助药物设计。在这方面,通过 AutoDock Vina 软件筛选了一个包含来自 Zinc 数据库的 15,387 种化学品的库。选定的命中 (ZINC59675144),根据其对接结合能并与阳性对照 (SB284485) 进行比较,进行分子动力学 (MD) 模拟。在 MD 之后,分析和讨论了游离或结合抑制剂的 YRS 复合物的理化参数。我们的分子模型研究以及 QM/MM 研究表明,ZINC59675144 作为 YRS 的潜在抑制剂具有令人印象深刻的特性,也可用作先导化合物以进一步改进。此外,ADME 分析显示整个理化特性与人类给药相容。表明 ZINC59675144 作为 YRS 的潜在抑制剂具有令人印象深刻的特性,也可用作先导化合物以进一步改进。此外,ADME 分析显示整个理化特性与人类给药相容。表明 ZINC59675144 作为 YRS 的潜在抑制剂具有令人印象深刻的特性,也可用作先导化合物以进一步改进。此外,ADME 分析显示整个理化特性与人类给药相容。
更新日期:2020-03-31
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