Natural Compounds as Inhibitors of SARS-CoV-2 Main Protease (3CLpro): A Molecular Docking and Simulation Approach to Combat COVID-19

Abstract

<p></p><p>Recently, the emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. In the fight against COVID-19, the rapid development of new drug molecules is the need of hour. However, the conventional approaches of drug development is time consuming and expensive in nature. In this study, we have adopted an alternative approach to identify lead molecules from natural sources using high throughput virtual screening approach. Ligands from natural compounds library from Selleck Inc (L1400) have been screened to evaluate their ability to bind and inhibit the main protease (M<sup>pro</sup> or 3CL<sup>pro</sup>) of SARS-CoV-2, which is a potential drug target. We found that Kaempferol, Quercetin, and Rutin were able to bind at the substrate binding pocket of 3CL<sup>pro</sup> with high affinity (10<sup>5</sup>-10<sup>6</sup> M<sup>-1</sup>) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin was much higher than Chloroquine (1000 times) and Hydroxychloroquine (100 times) and was comparable to that of the reference drug Remdesivir, which is in clinical trials to treat COVID-19 patients. The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.</p><br><p></p>

Bee products as a source of promising therapeutic and chemoprophylaxis strategies against COVID‐19 (SARS‐CoV‐2)

“…Moreover, a molecular docking study revealed that Kaempferol might also act on SARS‐CoV‐2 3CL pro , showing binding energy and binding affinity of −7.8 kcal/mol and 5.2 × 10 5 M −1 , respectively. It forms two hydrogen bonds, in which the one with the Gln189 residue described previously is critical to the catalytic activity of 3CL pro (Rehman et al, 2020).…”

“…Because SARS‐CoV‐2 3CL pro maintains the same residue Gln189 in its active site, it is suggested that the main protease of the novel coronavirus may also be sensitive to the inhibitory action of quercetin and its derivatives. Importantly, a recent computational study revealed that quercetin is predicted to form a hydrogen bond with Gln186 on active site of SARS‐CoV‐2 3CL pro , which results in low binding energy (−7.5 kcal/mol) and consequent high binding affinity (3.2 × 10 5 M −1 ) (Rehman, AlAjmi, & Hussain, 2020).…”

Phenolic compounds disrupt spike-mediated receptor-binding and entry of SARS-CoV-2 pseudo-virions

“…It is also a well-known fact that their adequate intake may help to modulate immune responses and resistance to infection. The efficacy of polyphenols as antiviral compounds has been frequently reported, and there is an enormous potential in exploring their antiviral properties, since they are commonly recognized as safe and effective in substituting for, or in serving as an adjunct treatment to, conventional therapies [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. Although, there is already substantial information about polyphenols' activity against SARS-CoV-2, most of these results are derived from computational modeling and computational predictions, and their capability as anti-SARS-CoV-2 agents still needs to be scientifically and clinically evaluated.…”

Exploring the treatment of COVID‐19 with Yinqiao powder based on network pharmacology

“…Some active ingredients found in Yinqiao powder by high‐performance liquid chromatography analysis may have anti‐COVID‐19 effects, such as rutin and hesperidin (Shu et al, 2012). Rehman, AlAjmi, and Hussain (2020) and Liang et al (2020) found that the binding affinity of rutin for the main protease (3CL pro ) of SARS‐CoV‐2 was much higher than that of chloroquine, hydroxychloroquine, and remdesivir, and it may inhibit COVID‐19 by downregulating IL‐6. Balmeh et al found that hesperidin has an inhibitory effect on human angiotensin‐converting enzyme 2 (ACE2), TMPRSS2, GRP78, and AT1R receptors and may have the ability to treat COVID‐19 infection (Balmeh, Mahmoudi, Mohammadi, & Karabedianhajiabadi, 2020).…”