在一组310天然抗病毒天然代谢物中,我们的团队确定了三种化合物是针对SARS-CoV-2主要蛋白酶(PDBID:5R84)的最有效的天然抑制剂,Mpro.鉴定的化合物是sattazolin和促乳素A和B。使用几种技术进行了验证的多阶段计算机研究。首先,将所选代谢物的分子结构与GWS的分子结构进行比较,Mpro的共结晶配体,在结构相似性研究中。该研究的目的是确定可以与类似于GWS的Mpro结合的30种最相似的代谢物(10%)。然后,针对Mpro的分子对接和药效团研究导致选择五种代谢物,这些代谢物对Mpro表现出良好的结合模式,对生成的药效团模型具有良好的拟合值。其中,根据ADMET研究选择了三种代谢物.通过毒性和DFT研究确定最有前途的Mpro抑制剂为催乳素A(292)。最后,对催乳素A进行了分子动力学(MD)模拟研究,以确认获得的结果并了解结合的热力学特性。希望通过对所选化合物进行进一步的体外和体内研究,取得的成果可以代表与COVID-19斗争的积极一步。
Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), Mpro. The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico
study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS, the co-crystallized ligand of Mpro, in a structural similarity
study. The aim of this
study was to determine the thirty most similar metabolites (10%) that may bind to the Mpro similar to GWS. Then, molecular docking against Mpro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the Mpro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising Mpro inhibitor was determined by toxicity and DFT studies to be caprolactin A (292). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds.