Medicinal Chemistry Research Laboratory, MNR College of Pharmacy, Sangareddy, 502 294, Gr. Hyderabad, India.
Department of Pharmacy, Pilani, Birla Institute of Technology & Sciences Pilani Campus, Pilani-333031, India.
Med Chem. 2023;19(9):925-938. doi: 10.2174/1573406419666230413112802.
A limited number of small molecules against SARS-CoV-2 has been discovered since the epidemic commenced in November 2019. The conventional medicinal chemistry approach demands more than a decade of the year of laborious research and development and a substantial financial commitment, which is not achievable in the face of the current epidemic.
This study aims to discover and recognize the most effective and promising small molecules by interacting SARS-CoV-2 M target through computational screening of 39 phytochemicals from five different Ayurvedic medicinal plants.
The phytochemicals were downloaded from Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) PubChem, and the SARS-CoV-2 protein (PDB ID: 6LU7; M) was taken from the PDB. The molecular interactions, binding energy, and ADMET properties were analyzed.
The binding affinities were studied using a structure-based drug design of molecular docking, divulging 21 molecules possessing greater to equal affinity towards the target than the reference standard. Molecular docking analysis identified 13 phytochemicals, sennoside-B (-9.5 kcal/mol), isotrilobine (-9.4 kcal/mol), trilobine (-9.0 kcal/mol), serratagenic acid (-8.1 kcal/mol), fistulin (-8.0 kcal/mol), friedelin (-7.9 kcal/mol), oleanolic acid (-7.9 kcal/mol), uncinatone (-7.8 kcal/mol), 3,4-di- O-caffeoylquinic acid (-7.4 kcal/mol), clemaphenol A (-7.3 kcal/mol), pectolinarigenin (-7.2 kcal/mol), leucocyanidin (-7.2 kcal/mol), and 28-acetyl botulin (-7.2 kcal/mol) from ayurvedic medicinal plants phytochemicals possess greater affinity than the reference standard Molnupiravir (-7.0 kcal/mol) against SARS-CoV-2-M.
Two molecules, namely sennoside-B, and isotrilobine with low binding energies, were predicted as most promising. Furthermore, we carried out molecular dynamics simulations for the sennoside-B protein complexes based on the docking score. ADMET properties prediction confirmed that the selected docked phytochemicals were optimal. These compounds can be investigated further and utilized as a parent core molecule to create novel lead molecules for preventing COVID-19.
自 2019 年 11 月疫情爆发以来，已发现了少量针对 SARS-CoV-2 的小分子。传统的药物化学方法需要超过十年的艰苦研发工作和大量的财务投入，而面对当前的疫情，这是无法实现的。
本研究旨在通过对来自五种不同阿育吠陀药用植物的 39 种植物化学物质进行计算机筛选，发现和识别与 SARS-CoV-2 M 靶标相互作用的最有效和最有前途的小分子。
从 Research Collaboratory for Structural Bioinformatics（RCSB）Protein Data Bank（PDB）PubChem 下载植物化学物质，从 PDB 中获取 SARS-CoV-2 蛋白（PDB ID：6LU7；M）。分析分子相互作用、结合能和 ADMET 特性。
使用基于结构的药物设计分子对接研究结合亲和力，揭示了 21 种分子对靶标具有比参考标准更大或相等的亲和力。分子对接分析鉴定了 13 种植物化学物质，番泻苷 B（-9.5 kcal/mol）、异千里光碱（-9.4 kcal/mol）、千里光碱（-9.0 kcal/mol）、蛇麻脂酸（-8.1 kcal/mol）、拳头（-8.0 kcal/mol）、friedelin（-7.9 kcal/mol）、齐墩果酸（-7.9 kcal/mol）、乌头酮（-7.8 kcal/mol）、3,4-二-O-咖啡酰奎宁酸（-7.4 kcal/mol）、香豆素酚 A（-7.3 kcal/mol）、pectolinarigenin（-7.2 kcal/mol）、白藜芦醇（-7.2 kcal/mol）和 28-乙酰 botulin（-7.2 kcal/mol）来自阿育吠陀药用植物的植物化学物质对 SARS-CoV-2-M 的亲和力大于参考标准 Molnupiravir（-7.0 kcal/mol）。
两种分子，即番泻苷 B 和异千里光碱，具有较低的结合能，被预测为最有前途的分子。此外，我们根据对接得分对番泻苷 B 蛋白复合物进行了分子动力学模拟。ADMET 特性预测证实，所选对接的植物化学物质是最佳的。这些化合物可以进一步研究，并用作预防 COVID-19 的新型先导分子的母体核心分子。
