(12в€’14) There are seven key drug targets for SARS-CoV-2, namely, (1) spike protein, (2) envelope protein, (3) membrane protein, (4) protease, (5) nucleocapsid protein, (6) hemagglutinin esterase, and (7) helicase. Protein targets for SARS-CoV-2 that are essential for the survival of the virus have been identified and are being used for drug discovery. Thus, the results demonstrate a synergistic mechanism between the two compounds that enhances the inhibition activity against SARS-CoV-2 3CL protease. Surface plasmon resonance was used to measure the binding of the compounds, and when used together, the compounds had a 10-fold greater binding affinity. Later, a multiconcentration assay was used to determine the coinhibitory activity, and it was observed that the compounds have в€ј20 to 30% inhibition activity even at lower concentrations of 0.5 and 1 ОјM. The enzyme assay exhibited 97 and 85% inhibition activity when both compounds were used together at 100 and 50 ОјM, respectively. However, the simulation showed that a simultaneous docked complex of both the compounds together with the protein boosts the stronger binding for a sufficient time. This suggests that while the ligands initially bind with the protease, they are unable to maintain it for an extended period. Comprehensive docking and molecular dynamics simulations elucidate that these compounds exhibit excellent binding in the process, which however quickly deteriorates, and the ligand is separated from the binding site.

Individually, they offer в€ј30 to 35% inhibition at 10 ОјM. The pair of compounds pursued in this study are flavonoid and naphthalene scaffold. The co-action of the two compounds, each derived from natural origins, has been demonstrated against the 3CL protease, already recognized as a potential drug target for inhibiting SARS-CoV-2. In this paper, we present a multicompound approach, where two drug molecules are administered concurrently to offer an effective therapy for COVID-19. This is relevant because the cost of production, storage, and ease of distribution of a small-molecule drug are significantly more favorable than those of biologics. While vaccines and other biotherapeutic products for managing COVID-19 have reached the market, a small-molecule cure is yet to be developed. The biggest challenge in medical management and control of the COVID-19 pandemic is the nonavailability of the treatment molecules.

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