Alkaloids and flavonoids from African phytochemicals as potential inhibitors of SARS-Cov-2 RNA-dependent RNA polymerase: anin silicoperspective

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.

In silico investigation to identify potential small molecule inhibitors of the RNA-dependent RNA polymerase (RdRp) nidovirus RdRp-associated nucleotidyltransferase domain

“…Various natural compounds have been examined for their ability to target the spike protein, M pro , papain-like protease (PL pro ), and RdRp, and further research is required to validate their antiviral effects and pharmacokinetic properties. Curcumin, piperine, demethoxycurcumin, glycyrrhizic acid, rutin, nicotiflorin, epigallocatechin-3-gallate, and theaflavin are natural compounds that have been identified as potential antiviral drugs against the SARS-CoV-2 RdRp based on in silico analysis [42] , [43] , [44] .…”

Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

“…An in-depth docking simulation of the phytocompounds and reference inhibitors was performed to optimize the docking experiment and interactions with the target protein using previously reported protocols [ 54 , 55 ]. Figure 2 shows the average binding affinities of the best ten phytocompounds along with the reference inhibitors (positive controls) against the five different representative conformations gotten from the clustering analysis of the SARS-CoV-2 3CL pro MDS trajectories (see Figure S3).…”

Implication of in silico studies in the search for novel inhibitors against SARS‐CoV‐2

“…[ 130,131 ] Ibrahim Khalifa et al examined 19 hydrolysable tannins against 3CLpro of SARS‐CoV‐2, and they found that of these (Figure 25), pedunculagin ( 205 ), tercatain ( 206 ) and castalin ( 207 ) showed the best binding affinities of −18.58, −23.11 and −14.04 kcal/mol, respectively, on the selected target. [ 132 ]…”