Virtual high throughput screening: Potential inhibitors for SARS-CoV-2 PLPRO and 3CLPRO proteases

Abstract

The pandemic, COVID-19, has spread worldwide and affected millions of people. There is an urgent need, therefore, to find a proper treatment for the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative agent. This paper focuses on identifying inhibitors that target SARS-CoV-2 proteases, PL PRO and 3CL PRO , which control the duplication and manages the life cycle of SARS-CoV-2. We have carried out detailed in silico Virtual high-throughput screening using Food and Drug Administration (FDA) approved drugs from the Zinc database, COVID-19 clinical trial compounds from Pubchem database, Natural compounds from Natural Product Activity and Species Source (NPASS) database and Maybridge database against PL PRO and 3CL PRO proteases. After thoroughly analyzing the screening results, we found five compounds, Bemcentinib, Pacritinib, Ergotamine, MFCD00832476, and MFCD02180753 inhibit PL PRO and six compounds, Bemcentinib, Clofazimine, Abivertinib, Dasabuvir, MFCD00832476, Leuconicine F inhibit the 3CL PRO . These compounds are stable within the protease proteins’ active sites at 20ns MD simulation. The stability is revealed by hydrogen bond formations, hydrophobic interactions, and salt bridge interactions. Our study results also reveal that the selected five compounds against PL PRO and the six compounds against 3CL PRO bind to their active sites with good binding free energy. These compounds that inhibit the activity of PL PRO and 3CL PRO may, therefore, be used for treating COVID-19 infection.

Dasabuvir Inhibits Human Norovirus Infection in Human Intestinal Enteroids

“…Indeed, there is a report showing that DSB partially inhibits the RdRp activity of Middle East respiratory syndrome coronavirus (MERS-CoV) ( 23 ). Targeting of viral protease might be another scenario for the inhibition; a very recent virtual screening study predicted that dasabuvir has the potential to inhibit 3-chymotrypsin-like protease (3CL PRO ) of SARS-CoV-2 ( 24 ).…”

In silico studies of selected xanthophylls as potential candidates against SARS-CoV-2 targeting main protease (Mpro) and papain-like protease (PLpro)

“…The main protease (Mpro) and the papain-like protease (PLpro) can be targets for anti-SARS-CoV-2 drugs. Research in this direction is prevalent and concerns mainly common natural compounds or repurposing of already used drugs [35][36][37][38]. Studies presented in this article are first concerning the activity of xanthophylls against SARS-CoV-2.…”

Hypericin Inhibit Alpha-Coronavirus Replication by Targeting 3CL Protease

“…Specifically, His41 and Cys144 were the key amino acids that have catalytic activity in PEDV and TGEV 3CLpro and form the S1 pocket together with Phe139, Ile140, Gly142, Ala143, His162, Gln163, Glu165, and His171 [ 33 , 48 ]. Meanwhile, several studies reported that natural compounds in traditional herbs could bind to the 3CLpro of CoV, leading to the inhibition of viral replication [ 49 , 50 , 51 , 52 , 53 ]; in particular, the natural compound, quercetin, inhibited the PEDV 3CLpro through Cys144, Asn141, and His162 that were located in S1 [ 33 , 54 ]. In this study, we found the Asn141 and Glu165 in solution 2 ( Figure 3 and Figure S2 ) were part of this S1 pocket, indicating hypericin indirectly inhibit the catalytic activity of 3CLpro in PEDV.…”