Discovery of compounds inhibiting SARS-COV-2 multi-targets.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic that has devastated the lives of millions. Researchers around the world are relentlessly working in hopes of finding a cure. Even though the virus shares similarities with reported SARS-CoV and MERS-CoV at the genomic and proteomic level, efforts to repurpose already known drugs against SARS-CoV-2 have resulted ineffective. In this succinct review, we discuss the different potential targets in SARS-CoV-2 at both the genomic and proteomic levels. In addition, we analyze the compounds inhibiting individual target protein as well as multiple targets of SARS-CoV-2. ACE-2 receptor in humans has also been considered a target, keeping the role of the receptor in mind. The mechanism of action of these compounds has also been highlighted along with their clinical manifestation. Towards the end of the review, a brief note on the drugs currently in clinical trials and the current status of the vaccines are also examined. In conclusion, compounds targeting multiple targets of the virus hold the key in putting an end to the coronavirus malady.Communicated by Ramaswamy H. Sarma.

Computational studies reveal Fluorine based quinolines to be potent inhibitors for proteins involved in SARS-CoV-2 assembly.

World is witnessing one of the worst pandemics of this century caused by SARS-CoV-2 virus which has affected millions of individuals. Despite rapid efforts to develop vaccines and drugs for COVID-19, the disease is still not under control. Chloroquine (CQ) and Hydroxychloroquine (HCQ) are two very promising inhibitors which have shown positive effect in combating the disease in preliminary experimental studies, but their use was reduced due to severe side-effects. Here, we performed a theoretical investigation of the same by studying the binding of the molecules with SARS-COV-2 Spike protein, the complex formed by Spike and ACE2 human receptor and a human serine protease TMPRSS2 which aids in cleavage of the Spike protein to initiate the viral activation in the body. Both the molecules had shown very good docking energies in the range of -6kcal/mol. Subsequently, we did a high throughput screening for other potential quinoline candidates which could be used as inhibitors. From the large pool of ligand candidates, we shortlisted the top three ligands (binding energy -8kcal/mol). We tested the stability of the docked complexes by running Molecular Dynamics (MD) simulations where we observed the stability of the quinoline analogues with the Spike-ACE2 and TMPRSS2 nevertheless the quinolines were not stable with the Spike protein alone. Thus, although the inhibitors bond very well with the protein molecules their intrinsic binding affinity depends on the protein dynamics. Moreover, the quinolines were stable when bound to electronegative pockets of Spike-ACE2 or TMPRSS2 but not with Viral Spike protein. We also observed that a Fluoride based compound: 3-[3-(Trifluoromethyl)phenyl]quinoline helps the inhibitor to bind with both Spike-ACE2 and TMPRSS2 with equal probability. The molecular details presented in this study would be very useful for developing quinoline based drugs for COVID-19 treatment.