Lather Amit, Sharma Sunil, Khatkar Anurag
Vaish Institute of Pharmaceutical Education and Research, Rohtak, India.
Department of Pharmaceutical Sciences, G.J.U.S.&T., Hisar, India.
Comb Chem High Throughput Screen. 2018;21(3):182-193. doi: 10.2174/1386207321666180330114457.
Infections caused by microorganisms are the major cause of death today. The tremendous and improper use of antimicrobial agents leads to antimicrobial resistance.
Various currently available antimicrobial drugs are inadequate to control the infections and lead to various adverse drug reactions. Efforts based on computer-aided drug design (CADD) can excavate a large number of databases to generate new, potent hits and minimize the requirement of time as well as money for the discovery of newer antimicrobials. Pharmaceutical sciences also have made development with advances in drug designing concepts. The current research article focuses on the study of various G-6-P synthase inhibitors from literature cited molecular database. Docking analysis was conducted and ADMET data of various molecules was evaluated by Schrodinger Glide and PreADMET software, respectively. Here, the results presented efficacy of various inhibitors towards enzyme G-6-P synthase. Docking scores, binding energy and ADMET data of various molecules showed good inhibitory potential toward G-6-P synthase as compared to standard antibiotics. This novel antimicrobial drug target G-6-P synthase has not so extensively been explored for its application in antimicrobial therapy, so the work done so far proved highly essential. This article has helped the drug researchers and scientists to intensively explore about this wonderful antimicrobial drug target.
The Schrodinger, Inc. (New York, USA) software was utilized to carry out the computational calculations and docking studies. The hardware configuration was Intel® core (TM) i5-4210U CPU @ 2.40GHz, RAM memory 4.0 GB under 64-bit window operating system. The ADMET data was calculated by using the PreADMET tool (PreADMET ver. 2.0). All the computational work was completed in the Laboratory for Enzyme Inhibition Studies, Department of Pharmaceutical Sciences, M.D. University, Rohtak, INDIA.
Molecular docking studies were carried out to identify the binding affinities and interaction between the inhibitors and the target proteins (G-6-P synthase) by using Glide software (Schrodinger Inc. U.S.A.-Maestro version 10.2). Grid-based Ligand Docking with Energetic (Glide) is one of the most accurate docking softwares available for ligand-protein, protein-protein binding studies. A library of hundreds of available ligands was docked against targeted proteins G-6-P synthase having PDB ID 1moq. Results of docking are shown in Table 1 and Table 2. Results of G-6-P synthase docking showed that some compounds were found to have comparable docking score and binding energy (kj/mol) as compared to standard antibiotics. Many of the ligands showed hydrogen bond interaction, hydrophobic interactions, electrostatic interactions, ionic interactions and π- π stacking with the various amino acid residues in the binding pockets of G-6-P synthase.
The docking study estimated free energy of binding, binding pose andglide score and all these parameters provide a promising tool for the discovery of new potent natural inhibitors of G-6-P synthase. These G-6-P synthase inhibitors could further be used as antimicrobials. Here, a detailed binding analysis and new insights of inhibitors from various classes of molecules were docked in binding cavity of G-6-P synthase. ADME and toxicity prediction of these compounds will further accentuate us to study these compounds in vivo. This information will possibly present further expansion of effective antimicrobials against several microbial infections.
微生物引起的感染是当今主要的死亡原因。抗菌药物的大量和不当使用导致了抗菌药物耐药性。
目前现有的各种抗菌药物不足以控制感染，并会导致各种药物不良反应。基于计算机辅助药物设计（CADD）的努力可以挖掘大量数据库，以产生新的、有效的命中物，并最大限度地减少发现新型抗菌药物所需的时间和金钱。药物科学也随着药物设计概念的进步而发展。当前的研究文章聚焦于从引用的分子数据库文献中研究各种6-磷酸葡萄糖合成酶抑制剂。分别通过Schrodinger Glide和PreADMET软件进行对接分析并评估各种分子的ADMET数据。在此，结果展示了各种抑制剂对6-磷酸葡萄糖合成酶的功效。与标准抗生素相比，各种分子的对接分数、结合能和ADMET数据显示出对6-磷酸葡萄糖合成酶具有良好的抑制潜力。这种新型抗菌药物靶点6-磷酸葡萄糖合成酶在抗菌治疗中的应用尚未得到广泛探索，因此迄今为止所做的工作被证明是非常必要的。本文有助于药物研究人员和科学家深入探索这个出色的抗菌药物靶点。
利用美国纽约的Schrodinger公司的软件进行计算和对接研究。硬件配置为英特尔®酷睿（TM）i5-4210U CPU @ 2.40GHz，在64位窗口操作系统下的随机存取存储器为4.0GB。使用PreADMET工具（PreADMET ver. 2.0）计算ADMET数据。所有计算工作均在印度罗塔克医学博士大学药学院酶抑制研究实验室完成。
使用Glide软件（美国Schrodinger公司-Maestro版本10.2）进行分子对接研究，以确定抑制剂与靶蛋白（6-磷酸葡萄糖合成酶）之间的结合亲和力和相互作用。基于网格的带能量的配体对接（Glide）是可用于配体-蛋白质、蛋白质-蛋白质结合研究的最精确的对接软件之一。将数百种可用配体的文库与具有PDB ID 1moq的靶蛋白6-磷酸葡萄糖合成酶进行对接。对接结果见表1和表2。6-磷酸葡萄糖合成酶对接结果表明，与标准抗生素相比，一些化合物具有相当的对接分数和结合能（千焦/摩尔）。许多配体与6-磷酸葡萄糖合成酶结合口袋中的各种氨基酸残基表现出氢键相互作用、疏水相互作用, 静电相互作用、离子相互作用和π-π堆积。
对接研究估计了结合自由能、结合姿势和Glide分数，所有这些参数为发现新型有效的6-磷酸葡萄糖合成酶天然抑制剂提供了一个有前景的工具。这些6-磷酸葡萄糖合成酶抑制剂可进一步用作抗菌剂。在此，对来自各类分子的抑制剂进行了详细的结合分析，并在6-磷酸葡萄糖合成酶的结合腔中获得了新的见解。这些化合物的ADME和毒性预测将进一步促使我们在体内研究这些化合物。这些信息可能会带来针对多种微生物感染的有效抗菌药物的进一步扩展。
