The Covid-19 pandemic, caused by SARS-Cov-2, is responsible for millions of deaths worldwide. Despite vaccines has already been developed, until date there is no specific therapeutic agent for this disease and hence, the scientific community is searching for potential antiviral agents against this virus. The main protease (Mpro) of SARS-Cov-2 is considered one of the important drug targets for treating Covid-19, since it plays a crucial role in the viral replication and transcription. A recent study showed that anisotine (1), which is one of some alkaloids from Justicia adhatoda and exhibits antiviral activity against herpes simplex virus (HSV), should be a potent Mpro inhibitor according to docking and molecular dynamic studies. In the present work, comparative molecular docking simulations of anisotine (1) and four oxoquinoline-acylhydrazone derivatives (2-5), were carried out in order to access their binding properties in the proposition of new potential candidates to Mpro inhibitors. Compounds 2, 3 and 4 have already been synthesized and showed anti-HIV-1 activity. They also have been tested in silico against HSV-1 DNA polymerase by our group, and compound 5 was proposed as a potential candidate to be a dual anti-HIV/HSV agent.
The outcomes of the docking generated by AutoDock Vina revealed that compound 4 has a good binding affinity with Mpro (-7,8 kcal/mol) when compared to anisotine (-7,9 kcal/mol). Furthermore, both of them interact with the catalytic residue Cys145. In addition to that, compound 4 had a higher number of intermolecular hydrogen bonds than anisotine, suggesting that it is a potential candidate to Mpro inhibitor such as anisotine. Analyzing the binding mode of compound 4 into the active site of Mpro, it was found that it interacts with at least three subsites similarly to Mpro’s substrate. The pharmacokinetic properties were evaluated using SwissADME online server and showed that none of the four compounds studied had Lipinski’s rules violation, which means that they probably will have good oral bioavailability.