Shakil Shazi, Danish Rizvi Syed M, Greig Nigel H
King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
R Soc Open Sci. 2023 Feb 8;10(2):221458. doi: 10.1098/rsos.221458. eCollection 2023 Feb.
Tackling the ever-looming threat of antibiotic resistance remains a challenge for clinicians and microbiologists across the globe. Sulfhydryl variable (SHV) is a known bacterial enzyme associated with antibiotic resistance. The SHV enzyme has many variants. The present article describes identification and molecular interaction of a putative inhibitor with the bacterial SHV enzyme as a step towards novel antibacterial drug discovery. The MCULE-platform was used for screening a collection of 5 000 000 ligand molecules to evaluate their binding potential to the bacterial SHV-1 enzyme. Estimation of pharmacokinetic features was realized with the aid of the 'SWISS ADME' tool. Toxicity-checks were also performed. The docked complex of 'the top screened out ligand' and 'the bacterial SHV-1 protein' was subjected to molecular dynamics simulation of 101 ns. The obtained ligand molecule, 1,1'-(4H,8H-Bis[1,2,5]oxadiazolo[3,4-b:3',4'-e]pyrazine-4,8-diyl)diethanone, displayed the most favourable binding interactions with bacterial SHV-1. A total of 15 amino acid residues were found to hold the ligand in the binding site of SHV-1. Noticeably, 12 of the 15 residues were found as common to the binding residues of the reference (PDB ID: 4ZAM). The RMSD values plotted against the simulation time showed that nearby 11 ns, equilibrium was reached and, thenceforth, the 'SHV-1-Top ligand' complex remained typically stable. Starting from around 11 ns and straight to 101 ns, the backbone RMSD fluctuations were found to be confined inside a range of 1.0-1.6 Å. The ligand, 1,1'-(4H,8H-Bis[1,2,5]oxadiazolo[3,4-b:3',4'-e]pyrazine-4,8-diyl)diethanone, satisfied ADMET criteria. Furthermore, the practicability of the described 'SHV-1-Top ligand' complex was reinforced by a comprehensive molecular dynamics simulation of 101 ns. This ligand hence can be considered a promising lead for antibiotic design against SHV-1 producing resistant bacteria, and thus warrants wet laboratory evaluation.
应对日益迫在眉睫的抗生素耐药性威胁，仍然是全球临床医生和微生物学家面临的一项挑战。巯基可变酶（SHV）是一种已知的与抗生素耐药性相关的细菌酶。SHV酶有许多变体。本文描述了一种假定抑制剂与细菌SHV酶的鉴定和分子相互作用，作为发现新型抗菌药物的一个步骤。利用MCULE平台筛选了500万个配体分子的集合，以评估它们与细菌SHV-1酶的结合潜力。借助“SWISS ADME”工具实现了药代动力学特征的估计。还进行了毒性检查。对“筛选出的顶级配体”和“细菌SHV-1蛋白”的对接复合物进行了101纳秒的分子动力学模拟。得到的配体分子1,1'-（4H,8H-双[1,2,5]恶二唑并[3,4-b:3',4'-e]吡嗪-4,8-二基）二乙酮与细菌SHV-1表现出最有利的结合相互作用。共发现15个氨基酸残基将配体固定在SHV-1的结合位点。值得注意的是，15个残基中的12个与参考（PDB ID：4ZAM）的结合残基相同。相对于模拟时间绘制的RMSD值表明，在接近11纳秒时达到平衡，此后，“SHV-1-顶级配体”复合物通常保持稳定。从大约11纳秒到101纳秒，主链RMSD波动被限制在1.0-1.6 Å的范围内。配体1,1'-（4H,8H-双[1,2,5]恶二唑并[3,4-b:3',4'-e]吡嗪-4,8-二基）二乙酮符合ADMET标准。此外，通过101纳秒的全面分子动力学模拟，增强了所描述的“SHV-1-顶级配体”复合物的实用性。因此，这种配体可以被认为是针对产生SHV-1耐药细菌的抗生素设计的一个有前景的先导物，因此值得进行湿实验室评估。
