Repurposing Multi-Targeting Plant Natural Product Scaffolds In Silico Against SARS-CoV-2 Non-Structural Proteins Implicated in Viral Pathogenesis

Abstract

<p>Background: Accessing COVID-19 vaccines is a challenge despite successful clinical trials. This burdens the COVID-19 treatment gap, thereby requiring accelerated discovery of anti-SARS-CoV-2 agents. Thus, this study explored the potential of anti-HIV reverse transcriptase (RT) phytochemicals as inhibitors of SARS-CoV-2 non-structural proteins (nsps) by targeting <i>in silico</i> key sites in the structures of SARS-CoV-2 nsps. Moreover, structures of the anti-HIV compounds were considered for druggability and toxicity. 104 anti-HIV phytochemicals were subjected to molecular docking with papain-like protease (nsp3), 3-chymotrypsin-like protease (nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13), SAM-dependent 2’-<i>O-</i>methyltransferase (nsp16) and its cofactor (nsp10), and endoribonuclease (nsp15). Drug-likeness and ADME (absorption, distribution, metabolism, and excretion) properties of the top ten compounds per nsp were predicted using SwissADME. Their toxicity was also determined using OSIRIS Property Explorer.</p> <p>Results: Among the twenty-seven top-scoring compounds, the polyphenolic natural products amentoflavone (<b>1</b>), robustaflavone (<b>4</b>), punicalin (<b>9</b>), volkensiflavone (<b>11</b>), rhusflavanone (<b>13</b>), morelloflavone (<b>14</b>), hinokiflavone (<b>15</b>), and michellamine B (<b>19</b>) were multi-targeting and had the strongest affinities to at least two of the nsps (Binding Energy = -7.7 to -10.8 kcal/mol). Friedelin (<b>2</b>), pomolic acid (<b>5</b>), ursolic acid (<b>10</b>), garcisaterpenes A (<b>12</b>), hinokiflavone (<b>15</b>), and digitoxigenin-3-<i>O-</i>glucoside (<b>17</b>) were computationally druggable. Moreover, compounds <b>5</b> and <b>17</b> showed good gastrointestinal absorptive property. Most of the compounds were also predicted to be non-toxic.</p> <p>Conclusions: Twenty anti-HIV RT phytochemicals showed multi-targeting inhibitory potential against SARS-CoV-2 nsp3, 5, 10, 12, 13, 15, and 16, and can therefore be used as prototypes for anti-COVID-19 drug design.</p>

Evaluation of the inhibitory potential of bioactive compounds against SARS-CoV-2 by in silico approach

“…Using the OSIRIS Property Explorer software, the analyzed compounds were screened, and only those that did not break Lipinski's rule were utilized to assess the mutagenic, reproductive hazards, irritating and tumorigenic, hydrophilicity, molecular weight, solubility, druglikeness, and drug score. Using the same software, solubility (Log S) was also predicted; Log S-4 denoted good solubility and favorable compound absorption [32].…”