猴痘病毒假定蛋白的功能特征和结构预测以及潜在抑制剂的鉴定。

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Reana Raen, Muhammad Muinul Islam, Redwanul Islam, Md Rabiul Islam, Tanima Jarin
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引用次数: 0

摘要

猴痘病毒(MPXV-Congo_8-156)的过度活化与各种皮肤和呼吸道疾病有关,如皮疹、充满液体的水疱、淋巴结肿大和脑炎(脑部炎症),这突出表明 MPXV-Congo_8-156 是一个很有希望的药物干预靶点。尽管西多福韦在抑制 MPXV 活性方面很有效,但其穿透皮肤的能力有限,而且副作用很大,这限制了它的应用。为了应对这一挑战,我们筛选了 500 种能够穿透皮肤和胃肠道的化合物,以确定强效的 MPXV 抑制剂。我们利用 PROTPARAM、SOPMA、SWISS-MODEL 和 PROCHECK 等生物信息学工具探索了 MPXV-Congo_8-156 的各种表征方案和结构模型。利用 PyRx 中的分子对接,我们评估了这些化合物与 MPXV-Congo_8-156 的结合亲和力,并确定了前五种候选化合物,其结合亲和力范围为 - 9.2 至 - 8.8 kcal/mol。ADMET 分析表明,这五种化合物都是更安全的替代品,在毒理学评估中未显示出 AMES 毒性或致癌性。分子动力学(MD)模拟各进行了 100 ns,证实了前五种化合物与对照组(西多福韦)的对接相互作用,验证了它们作为 MPXV 抑制剂的潜力。PubChem CID 编号为 4061636、4422538、3583576、4856107 和 4800629 的化合物在均方根偏差 (RMSD)、均方根波动 (RMSF)、回旋半径 (Rg)、可溶解表面积 (SASA) 值、氢键分析和分子力学泊松-波尔兹曼表面积 (MM-PBSA) 分析等方面都表现出很强的支持性。因此,我们的研究发现这五种化合物是很有前景的 MPXV 抑制剂,提供了潜在的治疗途径。然而,要验证我们的研究结果,还需要进一步的体内研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Functional characterization and structural prediction of hypothetical proteins in monkeypox virus and identification of potential inhibitors.

Functional characterization and structural prediction of hypothetical proteins in monkeypox virus and identification of potential inhibitors.

The excessive activation of the monkeypox virus (MPXV-Congo_8-156) is linked to various skin and respiratory disorders such as rashes, fluid-filled blisters, swollen lymph nodes and encephalitis (inflammation of the brain), highlighting MPXV-Congo_8-156 as a promising target for drug intervention. Despite the effectiveness of Cidofovir, in inhibiting MPXV activity, its limited ability to penetrate the skin and its strong side effects restrict its application. To address this challenge, we screened 500 compounds capable of penetrating the skin and gastrointestinal tract to identify potent MPXV inhibitors. Various characterization schemes and structural models of MPXV-Congo_8-156 were explored with bioinformatics tools like PROTPARAM, SOPMA, SWISS-MODEL and PROCHECK. Using molecular docking in PyRx, we evaluated the binding affinities of these compounds with MPXV-Congo_8-156 and identified the top five candidates ranging from - 9.2 to - 8.8 kcal/mol. ADMET analysis indicated that all five compounds were safer alternatives, showing no AMES toxicity or carcinogenicity in toxicological assessments. Molecular dynamics (MD) simulations, conducted for 100 ns each, confirmed the docking interactions of the top five compounds alongside the control (Cidofovir), validating their potential as MPXV inhibitors. The compounds with PubChem CID numbers 4061636, 4422538, 3583576, 4856107 and 4800629 demonstrated strong support in terms of root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA) value, hydrogen bond analysis, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis. Thus, our investigation identified these five compounds as promising inhibitors of MPXV, offering potential therapeutic avenues. However, further in vivo studies are necessary to validate our findings.

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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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