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In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the outbreak of a pulmonary disease called COVID-19, which killed thousands of people worldwide. Therefore, the necessity to find out the potential therapeutic pharmaceuticals is imperious. This study investigates the inhibitory effect of SARS-CoV-2 3-chymotrypsin-like protease (3CL pro ) using caffeine and caffeine-containing pharmaceuticals (3CPs) based on molecular dynamics simulations and free energy calculations by means of molecular mechanics-Poisson–Boltzmann surface area (MMPBSA) and molecular mechanics-generalized-Born surface area (MMGBSA). Of these 3CPs, seven drugs approved by the US-Food and Drug Administration have shown a good binding affinity to the catalytic residues of 3CL pro  of His 41  and Cys 145 : caffeine, theophylline, dyphylline, pentoxifylline, linagliptin, bromotheophylline and istradefylline. Their binding affinity score ranged from –4.9 to –8.6 kcal/mol. The molecular dynamic simulation in an aqueous solution of docked complexes demonstrated that the 3CPs conformations bound to the active sites of 3CL pro  during 200 ns molecular dynamics simulations. The free energy of binding also confirms the stability of the 3CPs–3CL pro  complexes. To our knowledge, this  in silico  study shows for the first time very inexpensive drugs available in large quantities that can be potential inhibitors against 3CL pro . In particular, the repurposing of linagliptin, and caffeine are recommended for COVID-19 treatment after  in vitro, in vivo  and clinical trial validation. Communicated by Ramaswamy H. Sarma

Caffeine and caffeine-containing pharmaceuticals as promising inhibitors for 3-chymotrypsin-like protease of SARS-CoV-2