Mebarka Ouassaf, Lotfi Bourougaa, Harun M Patel, Iqrar Ahmad, Bader Y Alhatlani
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引用次数: 0
摘要
本研究旨在鉴定在免疫原性靶向治疗中具有潜在应用价值的海洋来源蛋白酶抑制剂。方法:从基于GRL-09510复合物(PDB ID: 5v4y)的药效团模型开始,我们分离出三个关键特征(RAA),有助于从最初的18,547个化合物中选择192个候选化合物。结果:随后的对接分析显示,4个高亲和力化合物Echoside C (CMNPD22461)、Anguibactin (CMNPD3610)、Hansforester K (CMNPD30598)和Polyandocarpamide a (CMNPD4564)的结合评分分别为-7.773、-7.770、-7.690和-7.236 kcal/mol,均超过参比化合物的结合效率。进一步的药物相似度(ADME)和毒性谱的评估产生了有利的结果,并且从PASS程序预测的生物活性支持了它们作为有效蛋白酶抑制剂的潜力。密度泛函理论(DFT)分析和分子动力学模拟证实了这些化合物在与蛋白酶活性位点结合时的稳定性,其结构与GRL-09510复合物相似。结论:这些发现表明,所鉴定的海洋衍生化合物作为有效的蛋白酶抑制剂具有重要的前景,为免疫治疗和药物开发提供了新的机会。
An Integrated Computational Approach to Identify Potent HIV-1 Protease Inhibitors from Marine Sources.
Introduction: This study aimed to identify marine-derived protease inhibitors with potential applications in immunogenicity-targeted therapies.
Method: Starting with a pharmacophore model based on the GRL-09510 complex (PDB ID: 5v4y), we isolated three critical features (RAA) that facilitated the selection of 192 candidates from an initial pool of 18,547 compounds.
Results: Subsequent docking analyses, validated with a strong ROC value of 0.74, revealed four high-affinity compounds: Echoside C (CMNPD22461), Anguibactin (CMNPD3610), Hansforester K (CMNPD30598), and Polyandocarpamide A (CMNPD4564), with binding scores of -7.773, -7.770, -7.690, and -7.236 kcal/mol, respectively-each exceeding the reference compound's binding efficacy. Further assessments of drug-likeness (ADME) and toxicity profiles produced favorable results and predicted biological activity from the PASS program supported their potential as potent protease inhibitors. Density Functional Theory (DFT) analysis and molecular dynamics simulations confirmed the stability of these compounds when bound to the protease's active site, with configurations similar to the GRL-09510 complex.
Conclusion: These findings suggest that the identified marine-derived compounds hold significant promise as effective protease inhibitors, offering new opportunities for immunotherapy and advancements in drug development.
期刊介绍:
Combinatorial Chemistry & High Throughput Screening (CCHTS) publishes full length original research articles and reviews/mini-reviews dealing with various topics related to chemical biology (High Throughput Screening, Combinatorial Chemistry, Chemoinformatics, Laboratory Automation and Compound management) in advancing drug discovery research. Original research articles and reviews in the following areas are of special interest to the readers of this journal:
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