Alkaloids and flavonoids from African phytochemicals as potential inhibitors of SARS-Cov-2 RNA-dependent RNA polymerase: an in silico perspective

Abstract

Corona Virus Disease 2019 (COVID-19) is a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Exploiting the potentials of phytocompounds is an integral component of the international response to this pandemic. In this study, a virtual screening through molecular docking analysis was used to screen a total of 226 bioactive compounds from African herbs and medicinal plants for direct interactions with SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). From these, 36 phytocompounds with binding affinities higher than the approved reference drugs (remdesivir and sobosivir), were further docked targeting the active sites of SARS-CoV-2, as well as SARS-CoV and HCV RdRp. A hit list of 7 compounds alongside two positive controls (remdesivir and sofosbuvir) and two negative controls (cinnamaldehyde and Thymoquinone) were further docked into the active site of 8 different conformations of SARS-CoV-2 RdRp gotten from molecular dynamics simulation (MDS) system equilibration. The top docked compounds were further subjected to predictive druglikeness and ADME/tox filtering analyses. Drugable alkaloids (10'-hydroxyusambarensine, cryptospirolepine, strychnopentamine) and flavonoids (usararotenoid A, and 12α-epi-millettosin), were reported to exhibit strong affinity binding and interactions with key amino acid residues in the catalytic site, the divalent-cation-binding site, and the NTP entry channel in the active region of the RdRp enzyme as the positive controls. These phytochemicals, in addition to other promising antivirals such as remdesivir and sofosbuvir, may be exploited towards the development of a cocktail of anti-coronavirus treatments in COVID-19. Experimental studies are recommended to validate these study.

Keywords: RNA-dependent RNA polymerase; SARS-CoV-2; alkaloids; flavonoids; phytochemicals.

Figure 1.

Binding affinities of top phyto-compounds and reference compounds to the active site residues of viral RNA-dependent RNA polymerase. The red dotted line shows the top 3 docked alkaloids while blue dotted lines show the top 2 docked flavonoids.

Figure 2.

The top 5 phyto-compounds (10'-hydroxyusambarensine (gray), cryptospirolepine (blue), and strychnopentamine (yellow), usararotenoid A (green) and 12α-epi-millettosin (gold), docked into the active site of SARS-CoV-2 RdRp. The enlarged panel is depicted to show how the compounds are lying in the active site cavity of the protein.

Figure 3.

The interaction views of the best five compounds 10'-hydroxyusambarensine (gray), cryptospirolepine (blue), and strychnopentamine (yellow), usararotenoid A (green) and 12α-epi-millettosin (gold), against the active site of SARS-CoV-2 RdRp. H-bonds are depicted by the green dashed lines, while hydrophobic contacts in dashed-purple lines. Interacting residues are labelled with their three-letter codes.

Figure 4.

The average binding energies (in kcal/mol) of the 11 compounds against SARS-CoV-2 RdRp active site residue D760 and D761. Error bars represent the standard deviation (SD). The best two compounds are 10'-Hydroxyusambarensine and Cryptospirolepine (dark green columns) with average binding affinities of −10.08 Kcal/mol and −10.525 Kcal/mol, respectively.

Figure 5.

The interaction pattern for the docking of the best three compounds (10'_hydroxyusambarensine, cryptospirolepine, and strychnopentamine) against the active site of SARS-CoV-2 RdRp. H-bonds are depicted by blue lines, while hydrophobic contacts in dashed-gray lines. Salt-bridges are depicted in dashed-yellow lines between two yellow balls. π-cation interactions are in dashed-orange lines. Interacting residues are labelled with their one-letter codes and red-coloured. Coloured sticks represent both the compounds (yellow) and the interacting residues from SARS-CoV-2 RdRp (blue).

Figure 6.

The superposition of the docking complexes of the 10'-hydroxyusambarensine (yellow), cryptospirolepine (blue), and strychnopentamine (magenta), docked into the active site of SARS-CoV-2RdRp. The enlarged panel is depicted to show how the compounds are lying in the active site cavity of the protein.

Figure 7.

Summary of pharmacokinetic properties of the top, binding phytocompounds from African plants to the RdRp of SARS-Cov-2: (a) Usararotenoid A (b) 12α-epi-millettosin. The color space is the suitable physicochemical space for oral bioavailability LIPO Lipophility: -0.7 < XLOGP3 < +5.0 SIZE: 150g/mol: < MW < 500g/mol POLAR (Polarity): 20Ų < TPSA < 130 Å INSOLU (insolubility): 0 < Log S (ESOL) < 6 INSATU (insaturation): 0.25 < Fraction Csp3 <1 FLEX (Flexibity): 0 < Num. rotatable bonds < 9