Khan A, Shahab M, Nasir F, Waheed Y, Alshammari A, Mohammad A, Zichen G, Li R, Wei D Q
Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China.
Zhongjing Research and Industrialization Institute of Chinese Medicine, Zhongguancun Scientific Park, Nayang, P.R. China.
SAR QSAR Environ Res. 2023 Jul-Sep;34(9):689-708. doi: 10.1080/1062936X.2023.2250723. Epub 2023 Sep 7.
In the current study, we used molecular screening and simulation approaches to target I7L protease from monkeypox virus (mpox) from the Traditional Chinese Medicines (TCM) database. Using molecular screening, only four hits TCM27763, TCM33057, TCM34450 and TCM31564 demonstrated better pharmacological potential than TTP6171 (control). Binding of these molecules targeted Trp168, Asn171, Arg196, Cys237, Ser240, Trp242, Glu325, Ser326, and Cys328 residues and may affect the function of I7L protease in in vitro assay. Moreover, molecular simulation revealed stable dynamics, tighter structural packing and less flexible behaviour for all the complexes. We further reported that the average hydrogen bonds in TCM27763, TCM33057, TCM34450 and TCM31564I7L complexes remained higher than the control drug. Finally, the BF energy results revealed -62.60 ± 0.65 for the controlI7L complex, for the TCM27763I7L complex -71.92 ± 0.70 kcal/mol, for the TCM33057I7L complex the BF energy was -70.94 ± 0.70 kcal/mol, for the TCM34450I7L the BF energy was -69.94 ± 0.85 kcal/mol while for the TCM31564I7L complex the BF energy was calculated to be -69.16 ± 0.80 kcal/mol. Although, we used stateoftheart computational methods, these are theoretical insights that need further experimental validation.
在当前研究中，我们利用分子筛选和模拟方法，从传统中药（TCM）数据库中筛选针对猴痘病毒（mpox）I7L蛋白酶的药物。通过分子筛选，只有四个命中药物TCM27763、TCM33057、TCM34450和TCM31564显示出比TTP6171（对照）更好的药理潜力。这些分子与色氨酸168、天冬酰胺171、精氨酸196、半胱氨酸237、丝氨酸240、色氨酸242、谷氨酸325、丝氨酸326和半胱氨酸328残基结合，可能会在体外实验中影响I7L蛋白酶的功能。此外，分子模拟显示所有复合物都具有稳定的动力学、更紧密的结构堆积和更低的灵活性。我们进一步报告称，TCM27763、TCM33057、TCM34450和TCM31564与I7L形成的复合物中的平均氢键数量仍高于对照药物。最后，结合自由能（BF）结果显示，对照I7L复合物的BF能量为-62.60±0.65，TCM27763与I7L复合物的BF能量为-71.92±0.70千卡/摩尔，TCM33057与I7L复合物的BF能量为-70.94±0.70千卡/摩尔，TCM34450与I7L复合物的BF能量为-69.94±0.85千卡/摩尔，而TCM31564与I7L复合物的BF能量经计算为-69.16±0.80千卡/摩尔。尽管我们使用了最先进的计算方法，但这些都是理论见解，需要进一步的实验验证。
