Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

Abstract

SARS CoV-2 is the causative agent of the pandemic disease COVID-19. There is an urgent need for effective drugs or vaccines which can effectively combat this outbreak. The main protease (Mpro), a key component for the SARS CoV-2 replication, is considered to be one of the important drug targets for developing anti-COVID-19 drugs. This SARS CoV-2 Mpro/cysteine protease has high sequence similarity with the same protease from SARS CoV-1. Previously, it has been shown experimentally that eight diterpenoids and four biflavonoids derived from the leaf of Torreya nucifera show inhibitory effect on the cleavage/catalytic activity of the SARS CoV-1 Mpro. But whether these phytochemicals exhibit any inhibitory effect on SARS CoV-2 Mpro is unclear. To understand this fact, here, we have adopted various in-silico approaches. Diterpenoids and biflavonoids those qualified pharmacological test (hinokiol, amentoflavone, bilobetin and ginkgetin) and two well-known Mpro inhibitors (N3 and lopinavir) were subjected for molecular docking studies. Only three biflavonoids (amentoflavone, bilobetin and ginkgetin) were selected by comparing their binding affinities with N3 and lopinavir. They interacted with two most important catalytic residues of Mpro (His41 and Cys145). Molecular dynamics studies further revealed that these three Mpro-biflavonoid complexes are highly stable and share a similar degree of compactness. Besides, these complexes experience less conformational fluctuations and more expansion than Mpro-N3 and/or Mpro-lopinavir complex. MM-GBSA and H-bond analysis further corroborated these findings. Altogether, our study suggested that these three biflavonoids could possibly inhibit the proteolytic/catalytic activity of SARS CoV-2 Mpro and might be useful for COVID-19 treatment.

Phenolic compounds as antiviral agents: An In-Silico investigation against essential proteins of SARS-CoV-2

“…Rameshkumar et al (2021) reported that amentoflavone exhibited a binding affinity with a score of −8.1 kcal/mol against main protease. Consistently, additional work done on biflavonoids of Torreya nucifera leaves showed that amentoflavone had −9.2 kcal/mol binding affinity (Ghosh et al, 2020) .…”

In silico identification of natural products from Centella asiatica as severe acute respiratory syndromecoronavirus 2 main protease inhibitor

“…[ 5 ] On the other side, repurposing of various classes of natural products in several herbs for S-CoV-2 M pro inhibitor also showed promising results. These repurposings were mainly conducted through in silico approaches such as terpenoids from Cacospongia mycofijiensis ,[ 6 ] diterpenoids and bioflavonoids from Torreya nucifera ,[ 7 ] glycosylated flavonoids from various herbs, and saponins and tannins from various herbs. [ 8 ]…”

Combined use of the hepatitis C drugs and amentoflavone could interfere with binding of the spike glycoprotein of SARS-CoV-2 to ACE2: the results of a molecular simulation study

“…To the best of our knowledge, there are no other MD simulations of paritaprevir–RBD and amentoflavone–RBD complexes. But, there are many stable MD simulations of the amentoflavone complex with the main protease (Ghosh et al, 2020 ; Lokhande et al, 2020 ; Mishra et al, 2020 ; Patil et al, 2021 ; Saravanan et al, 2020 ; Swargiary et al, 2020 ). For paritaprevir and simeprevir, stable MD simulations with the main protease and the uridylate-specific endoribonuclease (NSP15) have been obtained (Alamri et al, 2020 ; Khan, Jha, Amera, et al, 2020 ; Khan, Jha, Singh, et al, 2020 ).…”

“…Besides, amentoflavone is an effective inhibitor (IC 50 ¼ 8.3 mM) of the SARS-CoV main protease (Ryu et al, 2010). In the recent in silico studies (Ghosh et al, 2020;Lokhande et al, 2020;Mishra et al, 2020;Patil et al, 2021;Peterson, 2020;Puttaswamy et al, 2020;Saravanan et al, 2020;Swargiary et al, 2020), amentoflavone has been reported to bind tightly to the main protease of SARS-CoV-2. There are also three docking studies targeting spike glycoprotein of SARS-CoV-2, in which amentoflavone was found among the hit compounds with the binding energies: À7.6 kcal/mol (Wei et al, 2020), À8.7 kcal/mol (Puttaswamy et al, 2020), and À10.2 kcal/mol (Rameshkumar et al, 2021).…”

“…Most of the molecular modeling studies against SARS-CoV-2 use the main protease as a drug target (Aanouz et al, 2020;Alamri et al, 2020;Badavath et al, 2020;Bhardwaj et al, 2020Bhardwaj et al, , 2021Ghosh et al, 2020;Jim enez-Alberto et al, 2020;Khan, Ali, et al, 2020;Kumar et al, 2020;Lokhande et al, 2020;Mishra et al, 2020;Saravanan et al, 2020). Perhaps this is because of the pivotal role of this enzyme in the virus life cycle and the high conservation of its active site (Ullrich & Nitsche, 2020).…”