Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran.
J Biomol Struct Dyn. 2023;41(21):11700-11713. doi: 10.1080/07391102.2022.2163425. Epub 2023 Jan 9.
The inhibition of protein-protein interactions (PPIs) by small molecules is an exciting drug discovery strategy. Here, we aimed to develop a pipeline to identify candidate small molecules to inhibit PPIs. Therefore, KPI, a Knowledge-based Protein-Protein Interaction Inhibition pipeline, was introduced to improve the discovery of PPI inhibitors. Then, phytochemicals from a collection of known Middle Eastern antiviral herbs were screened to identify potential inhibitors of key PPIs involved in COVID-19. Here, the following investigations were sequenced: 1) Finding the binding partner and the interface of the proteins in PPIs, 2) Performing the blind ligand-protein inhibition (LPI) simulations, 3) Performing the local LPI simulations, 4) Simulating the interactions of the proteins and their binding partner in the presence and absence of the ligands, and 5) Performing the molecular dynamics simulations. The pharmacophore groups involved in the LPI were also characterized. Aloin, Genistein, Neoglucobrassicin, and Rutin are our new pipeline candidates for inhibiting PPIs involved in COVID-19. We also propose KPI for drug repositioning studies.Communicated by Ramaswamy H. Sarma.
小分子抑制蛋白质-蛋白质相互作用（PPIs）是一种令人兴奋的药物发现策略。在这里，我们旨在开发一种识别候选小分子抑制 PPIs 的方法。因此，引入了基于知识的蛋白质-蛋白质相互作用抑制（KPI）管道，以提高 PPI 抑制剂的发现。然后，筛选了一系列已知的中东抗病毒草药中的植物化学物质，以鉴定潜在的 COVID-19 关键 PPI 的抑制剂。在此，按以下顺序进行了调查：1）寻找 PPIs 中蛋白质的结合伴侣和界面，2）进行盲配体-蛋白抑制（LPI）模拟，3）进行局部 LPI 模拟，4）模拟蛋白质及其结合伴侣在配体存在和不存在的情况下的相互作用，5）进行分子动力学模拟。还对 LPI 中涉及的药效团基团进行了表征。芦荟素、染料木黄酮、新葡萄糖异硫氰酸酯和芦丁是我们用于抑制 COVID-19 相关 PPI 的新管道候选物。我们还提出了 KPI 用于药物重新定位研究。由 Ramaswamy H. Sarma 传达。
