Future appeal of comparative studies on putative binding sites of HIV-1 virus-encoded proteolytic enzyme inhibitor of different Food and Drug Administration-approved compounds

IF 0.3 Q4 INFECTIOUS DISEASES
Z. Abduljaleel, M. Athar, F. Al-Allaf, Saied Al-Dehlawi, Sami Melebari, W. El‐Huneidi
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Abstract

Introduction: Human immunodeficiency virus (HIV) protease enzyme is one of the most promising therapeutic targets for acquired immunodeficiency syndrome (AIDS) treatment. Due to mutation of the virus, there is always a room for new agents. Material and methods: The aim of in silico molecular docking study was to analyze and compare the binding mode of seven Food and Drug Administration (FDA)-approved HIV protease enzyme inhibitors, and to understand their structural requirements to inhibit an enzyme by using Schrodinger model as well as to evaluate a free energy of binding of these inhibitors with an enzyme. Results: The binding mode analysis showed that the active site was present at the interface of two chains A and B of the enzyme and the crucial amino acid remained responsible for the binding of inhibitors to the HIV-1 protease, which could help to classify the inhibitors as better drug targets. Results of this comparative binding mode analysis of seven FDA-approved drugs could be potential and useful for designing of a new effective inhibitor of HIV-1 protease. Out of seven inhibitors drugs, only two drugs present the best inhibition. HIV protease-nelfinavir complex with PDB: 2Q64 and HIV protease D30N, and R41A double mutant-tipranavir complex in PDB: 1D4S double mutant V82F and I84V, were used as templates for applying the mutations on HIV protease active site. Furthermore, the structure-based computer-assisted search for the comparison of the two inhibitors of HIV protease was completed. On the other hand, tipranavir seems to be a broad specificity inhibitor, as no changes in the bond lengths with the introduction of mutations were observed. Conclusions: Tipranavir could be targeted more effectively for designing future drug analogues, as it is less vulnerable to mutations. HIV mutants reported in this study could also be used for preliminary identification of specific inhibitors, as drugs that may alter the HIV protease activity for medicinal use. HIV AIDS Rev 2020; 19, 2: 78-86 DOI: https://doi.org/10.5114/hivar.2020.96402
不同食品和药物管理局批准的化合物对HIV-1病毒编码的蛋白水解酶抑制剂的推定结合位点的比较研究的未来呼吁
人类免疫缺陷病毒(HIV)蛋白酶是治疗获得性免疫缺陷综合征(AIDS)最有希望的治疗靶点之一。由于病毒的变异,总会有新的病原体出现的空间。材料和方法:硅分子对接研究的目的是分析和比较美国食品和药物管理局(FDA)批准的7种HIV蛋白酶抑制剂的结合模式,并利用薛定谔模型了解其抑制酶的结构要求,并评估这些抑制剂与酶的结合自由能。结果:结合模式分析表明,活性位点存在于酶的A和B两条链的界面上,并且关键氨基酸仍然负责抑制剂与HIV-1蛋白酶的结合,这有助于将抑制剂分类为更好的药物靶点。这7种fda批准的药物的比较结合模式分析的结果可能对设计一种新的有效的HIV-1蛋白酶抑制剂有潜在的和有用的。在7种抑制剂药物中,只有两种药物表现出最好的抑制作用。以PDB: 2Q64和HIV蛋白酶D30N的HIV蛋白酶-奈非那韦复合物,以及PDB: 1D4S双突变体V82F和I84V的R41A双突变体-替那韦复合物作为模板,将突变应用于HIV蛋白酶活性位点。此外,完成了基于结构的计算机辅助搜索,以比较两种HIV蛋白酶抑制剂。另一方面,替普那韦似乎是一种广泛特异性抑制剂,因为没有观察到随着突变的引入而改变键长。结论:替普那韦可以更有效地设计未来的药物类似物,因为它不易受突变的影响。本研究中报道的HIV突变体也可用于初步鉴定特异性抑制剂,作为可能改变HIV蛋白酶活性的药物。艾滋病Rev 2020;[j] .中国科学:地球科学
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来源期刊
HIV & AIDS Review
HIV & AIDS Review INFECTIOUS DISEASES-
CiteScore
0.50
自引率
0.00%
发文量
30
审稿时长
12 weeks
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