Department of Biochemistry and Molecular Biology 1, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Department of Genetics and Bioinformatics 2, Dasman Diabetes Institute, Dasman 15462, Kuwait.
Biomolecules. 2021 Apr 14;11(4):573. doi: 10.3390/biom11040573.
The SARS-CoV-2 non-structural protein (nsp) nsp10-nsp16 complex is essential for the 2'-O-methylation of viral mRNA, a crucial step for evading the innate immune system, and it is an essential process in SARS-CoV-2 life cycle. Therefore, detecting molecules that can disrupt the nsp10-nsp16 interaction are prospective antiviral drugs. In this study, we screened the North African Natural Products database (NANPDB) for molecules that can interact with the nsp10 interface and disturb the nsp10-nsp16 complex formation. Following rigorous screening and validation steps, in addition to toxic side effects, drug interactions and a risk /benefit assessment, we identified four compounds (genkwanin-6-C-beta-glucopyranoside, paraliane diterpene, 4,5-di-p-trans-coumaroylquinic acid and citrinamide A) that showed the best binding affinity and most favourable interaction with nsp10 interface residues. To understand the conformational stability and dynamic features of nsp10 bound to the four selected compounds, we subjected each complex to 200 ns molecular dynamics simulations. We then calculated the free binding energies of compounds interacting with nsp10 structure using the molecular mechanics-generalised Born surface area (MMGBSA). Of the four compounds, genkwanin-6-C-beta-glucopyranoside demonstrated the most stable complex with nsp10, in addition to a tighter binding affinity of -37.4 ± 1.3 Kcal/mol. This potential to disrupt the nsp10-nsp16 interface interaction and inhibit it now sets the path for functional studies.
SARS-CoV-2 的非结构蛋白（nsp）nsp10-nsp16 复合物是病毒 mRNA 2'-O-甲基化所必需的，这是逃避先天免疫系统的关键步骤，也是 SARS-CoV-2 生命周期中的一个重要过程。因此，检测能够破坏 nsp10-nsp16 相互作用的分子是有前途的抗病毒药物。在这项研究中，我们筛选了北非天然产物数据库（NANPDB），以寻找能够与 nsp10 界面相互作用并干扰 nsp10-nsp16 复合物形成的分子。经过严格的筛选和验证步骤，除了毒性副作用、药物相互作用和风险/收益评估外，我们确定了四种化合物（根皮苷-6-C-β-吡喃葡萄糖苷、 paraliane 二萜、4,5-二-p-反式-肉桂酰奎宁酸和 citrinamide A），它们与 nsp10 界面残基具有最佳的结合亲和力和最有利的相互作用。为了了解与四种选定化合物结合的 nsp10 的构象稳定性和动态特征，我们对每个复合物进行了 200 ns 的分子动力学模拟。然后，我们使用分子力学-广义 Born 表面积（MMGBSA）计算了与 nsp10 结构相互作用的化合物的自由结合能。在这四种化合物中，根皮苷-6-C-β-吡喃葡萄糖苷与 nsp10 形成的复合物最稳定，结合亲和力也更强，为-37.4±1.3 Kcal/mol。这种破坏 nsp10-nsp16 界面相互作用并抑制其的潜力为功能研究开辟了道路。
