Finding potent inhibitors for COVID-19 main protease (M^pro): anin silicoapproach using SARS-CoV-3CL protease inhibitors for combating CORONA

Abstract

SARS-CoV-2 is liable for the worldwide coronavirus disease (COVID-19) exigency. This pandemic created the need for all viable treatment strategies available in the market. In this scenario, computeraided drug design techniques can be efficiently applied for the quick identification of promising drug repurposing candidates. In the current study, we applied the molecular docking approach in conjugation with molecular dynamics (MD) simulations to find out potential inhibitors against M pro of SARS-CoV-2 from previously reported SARS-3CL protease inhibitors. Our results showed that N-substituted isatin derivatives and pyrazolone compounds could be used as a potent inhibitor and may possess an anti-viral activity against SARS-CoV-2. However, further experimental investigation and validation of the selected hits are required to find out their suitability for clinical trials.

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations

“…The Mpro plays a major role in mediating the replication and transcription of SARS-CoV-2. The mutagenesis rate is low in the Mpro, and it cleaves the pp1a and pp1b polyproteins, which release functional proteins, including RNA polymerase, exoribonuclease, and endoribonuclease [ 5 , 6 ]. Moreover, Mpro inhibitors are considered less cytotoxic because of the low similarity between Mpro and human proteases [ [7] , [8] , [9] ].…”

“…Moreover, Mpro inhibitors are considered less cytotoxic because of the low similarity between Mpro and human proteases [ [7] , [8] , [9] ]. Therefore, the Mpro is a promising target for drugs with which to treat coronaviruses, and the inhibition of Mpro activity is vital to blocking coronavirus replication [ 5 , 9 , 10 ].…”

“…To date, several studies have focused on the inhibition of Mpro activity [ [5] , [6] , [7] ]. Pendyala et al [ 11 ] conducted molecular docking studies to identify potential inhibitors for the Mpro and the RNA-dependent RNA polymerase in bioactive food compounds.…”

Vitamin D is a New Promising Inhibitor to the Main Protease (Mpro) of COVID-19 by Molecular Docking

“…With this regard many in silico studies were conducted to show and evaluate the efficacy of some active ingredients like flavonoids and some other natural products against SARS-CoV-2 M pro utilizing molecular docking technique. Taking in consideration the relative safe profile of these natural ingredients, these compounds could be be held in future as an outset for new therapeutics against COVID-19 [6,21]. In our previous study on the efficacy of vitamin D as is a potential inhibitor of SARS-CoV-2 endoribonuclease Nsp15, we found that Vitamin D is uniquely suppressed the three active sites in Nsp15 with significant advantageousness when compared to the other drugs utilized in treatment of COVID-19 like Remdesivir, Chloroquine, and Hydroxychloroquine [20].…”

“…In addition, the pp1a and pp1ab polyproteins in 16 different nonstructural proteins are also processed by M pro . These non-structural proteins are involved in the construction of subgenomic RNAs encoding four main structural proteins namely spike (S), nucleocapsid protein (N), envelope (E), and membrane (M) as well as the other accessory proteins [6].…”