Neurotransmitter-coumarin derivatives as potential SARS-CoV-2 main protease inhibitors

Coronavirus outbreak has influenced the global economy and everyday life of millions of people. The quest for the vaccine has already started but the limitations in productions and trial period made scientists look for alternatives, especially among naturally occurring molecules with proven biological significance. In this contribution, three recently synthesized coumarin derivatives with dopamine, norepinephrine, and octopamine were subjected to the molecular docking study and inhibitory activity determination towards SARS-CoV-2 main protease. All of the investigated molecules possess the rigid part which consists of fused heterocyclic/aromatic rings and a flexible part with electronegative atoms, therefore the study aims to provide answers about the importance of these moieties for the inhibitory activity. The results showed that coumarin derivatives with neurotransmitters have the binding energies between -39.83 and -46.26 kJ mol^-1, as opposed to cinanserin (-43.56 kcal mol^-1) and remdesivir (-60.08 kcal mol^-1). The special emphasis in the discussion was put on the possibility of hydrogen bond formation, overall flexibility of molecules, and the position of OH groups. Based on the Fukui functions, the most active positions for electrophilic attack include aromatic OH groups of neurotransmitters and the carbonyl oxygen of coumarin. The probable nucleophilic and radical attack positions are carbon atoms of the rigid part with extended delocalization and carbonyl oxygen. The aliphatic OH groups lowered the flexibility and led to a decrease in the binding energy. Because all three derivatives passed the Lipinski rule of five, it is believed that further theoretical and experimental studies should be undertaken.