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

Journal Article · Wed Aug 11 00:00:00 EDT 2021 · Journal of Fluorine Chemistry

DOI:https://doi.org/10.1016/j.jfluchem.2021.109865· OSTI ID:1981666

Sarkar, Neellohit ^[1]; Thakur, Abhimanyu ^[2]; Ghadge, Jigisha ^[2]; Rath, Soumya Lipsa ^[1]

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1. National Institute of Technology Warangal (NITW), Telangana (India)
2. Sinhgad Technical Education Society, Maharashtra (India)

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.

• Research Organization: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
• Sponsoring Organization: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
• Grant/Contract Number: AC02-05CH11231
• OSTI ID: 1981666
• Journal Information: Journal of Fluorine Chemistry, Journal Name: Journal of Fluorine Chemistry Journal Issue: C Vol. 250; ISSN 0022-1139
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Chemistry
Chloroquine
Hydroxychloroquine
Molecular dynamics
Spike-ACE2
TMPRSS2
Virtual screening