Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach

Abstract

Ul-Haq (2020): Identification of chymotrypsin-like protease inhibitors of SARS-CoV-2 via integrated computational approach, Journal of Biomolecular Structure and Dynamics, ABSTRACT Recently, the world has witnessed outbreak of a novel Coronavirus (SARS-CoV-2), the virus which initially emerged in Wuhan, China has now made its way to a large part of the world, resulting in a public emergency of international concern. The functional importance of Chymotrypsin-like protease (3CL pro ) in viral replication and maturation turns it into an attractive target for the development of effective antiviral drugs against SARS and other coronaviruses. At present, there is no standard drug regime nor any vaccine available against the infection. The rapid development and identification of efficient interventions against SARS-CoV-2 remains a major challenge. Based on the available knowledge of closely related coronavirus and their safety profiles, repurposing of existing antiviral drugs and screening of available databases is considered a near term strategic and economic way to contain the SARS-CoV-2 pandemic. Herein, we applied computational drug design methods to identify Chymotrypsin-like protease inhibitors from FDA approved antiviral drugs and our in-house database of natural and drug-like compounds of synthetic origin. As a result three FDA approved drugs (Remdesivir, Saquinavir and Darunavir) and two natural compounds (. flavone and coumarine derivatives) were identified as promising hits. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior, stability of protein-ligand contact, and binding affinity of the hit compounds. Our results indicate that the identified compounds can inhibit the function of Chymotrypsin-like protease (3CL pro ) of Coronavirus. Considering the severity of the spread of coronavirus, the current study is in-line with the concept of finding the new inhibitors against the vital pathway of the corona virus to expedite the process of drug discovery.

Andrographolide as a potential inhibitor of SARS-CoV-2 main protease: an in silico approach

“…guidetopharmacology.org/coronavirus.jsp) are in the process of being found in order to decrease the prognosis of the disease and life cycle of the virus. In silico studies of chemically synthetic drugs such as Paritaprevir and Raltegravir, Doultegravir and Bictegravir for the targets 3CLpro and 2 0 -OMTase (Khan, Jha, et al, 2020), theophylline and pyrimidone derivatives as possible inhibitors of RNA bound N terminal domain (Sarma et al, 2020) and Remdesivir, Saquinavir and Darunavir also with two natural compounds, flavone and coumarine derivatives for the inhibition of 3CL pro (Khan, Zia, et al, 2020) have been published. Though there are many targets are found for the treatment of COVID-19, the main protease (M pro ) of SARS-CoV-2 was chosen due to interest of treating infected patients, to stop the multiplication of virus within the cells, through which M pro was involved in the release of polypeptides which are functional extensive proteolysis and cleavage of the enzyme itself from the sites of genome, pp1a and ppa1ab .…”

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an in silico perspective

“…(Doublie & Ellenberger, 1998;Elfiky, 2020a;Elfiky & Ismail, 2018). Several studies are suggesting the effectiveness of different anti-viral drugs and compounds against the coronavirus proteins (Aanouz et al, 2020;Boopathi et al, 2020;Elfiky & Azzam, 2020;Elmezayen et al, 2020;Enayatkhani et al, 2020;Gupta et al, 2020;Khan et al, 2020aKhan et al, , 2020bMuralidharan et al, 2020;Pant et al, 2020;Sarma et al, 2020).…”

A molecular modeling approach to identify effective antiviral phytochemicals against the main protease of SARS-CoV-2

“…The SARS-CoV-2 Main protease (Mpro) monomer consists of N-terminal domain-I, N-terminal domain-II, and C-terminal domain-III (Mirza & Froeyen, 2020). The active site of enzyme contains a catalytic dyad having Cys145 and His41 (Bacha et al, 2004;Khan, Zia, et al, 2020). HIV drugs including lopinavir and ritonavir have been explored recently against MERS-CoV (Sheahan et al, 2020).…”