ALPHA-VINIFERIN AND NEOHESPERIDIN AS POTENTIAL 3CLPRO INHIBITORS OF SARS-COV-2: AN IN-SILICO VIRTUAL SCREENING INVESTIGATION

Abstract

As of December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged causing the third outbreak of coronavirus that our planet still suffers until today. To date, no effective therapy has been approved for its treatment, which suggests the need to broaden the search scope for an efficient remedy. In the current work, we evaluated in-silico a total of 4,028 natural isolated compounds from NADI database (www.nadi-discovery.com) as potential inhibitors of the CoV-2 3C-like main protease (3CL^pro). Virtual screening study of the compounds revealed 47 molecules which bind with a lowest-energy-of-binding (LEB) range of -9.30 to -10.90 kcal/mol indicating an equal and/or higher binding affinities compared to the control peptide inhibitor (N3). Furthermore, molecular docking simulations of these compounds showed that only 16 of them managed to reach a LEB range of -10.11 to -12.47 kcal/mol that is comparable to that of the control. Studying the compounds interactions at the main binding pocket of 3CL^pro, it has been found that all the 16 compounds managed to successfully interact with both residues of the catalytic dyad of the protein; His41 and Cys145, which are essential for the proteolytic activity of the proteinase. However, only two compounds successfully interacted with these residues through hydrogen-bonding. Alpha-viniferin (from the barks of Dryobalanops aromatica and Shorea gibbosa) has managed to bind forming seven hydrogen bonds (LEB = -12.46 kcal/mol) with a K_i value of 726.61 pM, whereas neohesperidin (from the fruits and peels of Citrus aurantium and Citrus limon) has managed to bind with eight hydrogen bonds (LEB = -10.60 kcal/mol) with a K_i value of 17.07 nM. Thus, we present our findings which suggest that these two natural compounds might have the potentials to be used in the prevention and treatment of CoV-2 through inhibiting the activity of 3CL^pro.