当前COVID-19的爆发正在引领一项前所未有的科学努力,专注于靶向对其病毒复制至关重要的SARS-CoV-2蛋白。在这里,我们使用基于反向传播的人工神经网络(q2LOO=0.60,r2=0.80和r2pred=0.91)对超过11000种FDA批准的药物进行了高通量虚拟筛选,偏最小二乘(PLS)回归(q2LOO=0.83,r2=0.62和r2pred=0.70)和序贯最小优化(SMO)回归(q2LOO=0.70,r2=0.80和r2pred=0.89)。我们模拟了阿卡波糖衍生的六糖的稳定性,那拉曲普坦,帕拉米韦,双氢链霉素,Enviomycin,罗利特环素,紫霉素,血管紧张素II,血管紧张素1-7,血管紧张素酰胺,非诺特罗,扎那米韦,Laninamivir和Laninamivir辛酸盐与3CLpro的100ns,并使用分子力学结合泊松-玻尔兹曼表面积(MM-PBSA)计算结合自由能。我们的QSAR模型和分子动力学数据表明,七种再利用的候选药物,如阿卡波糖衍生的六糖,血管紧张酰胺,双氢链霉素,Enviomycin,非诺特罗,那曲普坦和紫霉素是潜在的SARS-CoV-2主要蛋白酶抑制剂。此外,我们的QSAR模型和分子动力学模拟显示,His41,Asn142,Cys145,Glu166和Gln189是3CLpro抑制剂的潜在药效中心.Glu166是药物设计的潜在药效团,与该残基相互作用的抑制剂可能是避免3CLpro二聚化的关键。我们的结果将有助于未来对新型化学支架的研究以及在高通量筛选中发现新型命中物作为潜在的抗SARS-CoV-2特性。由RamaswamyH.Sarma沟通。
The current outbreak of COVID-19 is leading an unprecedented scientific effort focusing on targeting SARS-CoV-2 proteins critical for its viral replication. Herein, we performed high-throughput virtual screening of more than eleven thousand FDA-approved drugs using backpropagation-based artificial neural networks (q2LOO = 0.60, r2 = 0.80 and r2pred = 0.91), partial-least-square (PLS) regression (q2LOO = 0.83, r2 = 0.62 and r2pred = 0.70) and sequential minimal optimization (SMO) regression (q2LOO = 0.70, r2 = 0.80 and r2pred = 0.89). We simulated the stability of Acarbose-derived hexasaccharide, Naratriptan, Peramivir, Dihydrostreptomycin, Enviomycin, Rolitetracycline, Viomycin, Angiotensin II, Angiotensin 1-7, Angiotensinamide,
Fenoterol, Zanamivir, Laninamivir and Laninamivir octanoate with 3CLpro by 100 ns and calculated binding free energy using molecular mechanics combined with Poisson-Boltzmann surface area (MM-PBSA). Our QSAR models and molecular dynamics data suggest that seven repurposed-drug candidates such as Acarbose-derived Hexasaccharide, Angiotensinamide, Dihydrostreptomycin, Enviomycin,
Fenoterol, Naratriptan and Viomycin are potential SARS-CoV-2 main protease inhibitors. In addition, our QSAR models and molecular dynamics simulations revealed that His41, Asn142, Cys145, Glu166 and Gln189 are potential pharmacophoric centers for 3CLpro inhibitors. Glu166 is a potential pharmacophore for drug design and inhibitors that interact with this residue may be critical to avoid dimerization of 3CLpro. Our results will contribute to future investigations of novel chemical scaffolds and the discovery of novel hits in high-throughput screening as potential anti-SARS-CoV-2 properties.Communicated by Ramaswamy H. Sarma.