The ongoing monkeypox virus outbreak emerged in 2022 during the COVID-19 pandemic demonstrated a potential threat of this viral zoonosis to public health. To date no specific treatments either small molecule or vaccines against this infection are available except a supportive therapy. Considering the success of inhibitor discovery by targeting the viral proteases i.e., HIV, Hepatitis C, and SARS-CoV-2, we also targeted I7L protease from monkeypox virus (mpox) to design and develop of specific and compelling drugs from traditional Chinese medicine (TCM) database against this emerging disease. Using molecular screening, only four hits TCM27763, TCM33057, TCM34450 and TCM31564 demonstrated better pharmacological potential than the TTP-6171, the only non-covalent I7L protease inhibitor taken as control. Binding mode of each of the top hit revealed that these compounds block the main active site residues i.e., Trp168, Asn171, Arg196, Cys237, Ser240, Trp242, Glu325, Ser326, and Cys328 and block the function of I7L protease. Moreover, molecular simulation revealed that the identified compounds exhibit stable dynamics and may induce stronger therapeutic effects in experimental setup. All the complexes reported tighter structural packing and less flexible behaviour. We found that the average hydrogen bonds in TCM27763, TCM33057, TCM34450 and TCM31564-I7L complexes remained higher than the control drug. Finally, the total binding free energy demonstrated the best hits among the all. The BF energy results revealed -62.60 ± 0.65 for the control-I7L complex, for the TCM27763-I7L complex -71.92 ± 0.70 kcal/mol, for the TCM33057-I7L complex the BF energy was -70.94 ± 0.70 kcal/mol, for the TCM34450-I7L the BF energy was -69.94 ± 0.85 kcal/mol while for the TCM31564-I7L complex the BF energy was calculated to be -69.16 ± 0.80 kcal/mol. Although, we used state-of-the-art computational methods but these are theoretical insights and need further experimental validation.
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