In Silico Identification of Potent COVID-19 Main Protease Inhibitors from FDA Approved Antiviral Compounds and Active Phytochemicals through Molecular Docking: A Drug Repurposing Approach

Abstract

The Novel Coronavirus (COVID-19) is a positive-sense single-stranded RNA ((+)ssRNA) virus. The COVID-19 Main Proteases play very important role in the propagation of the Novel Coronavirus (COVID-19). It has already killed more than 8000 people around the world and thousands of people are getting infected every day. Therefore, it is very important to identify a potential inhibitor against COVID-19 Main Proteases to inhibit the propagation of the Novel Coronavirus (COVID-19). We have applied a drug repurposing approach of computational methodology, depending on the synergy of molecular docking and virtual screening techniques, aimed to identify possible potent inhibitors against Novel Coronavirus (COVID-19) from FDA approved antiviral compounds and from the library of active phytochemicals. On the basis of recently resolved COVID-19 Main Protease crystal structure (PDB:6LU7), the library of 100 FDA approved antiviral compounds and 1000 active components of Indian Medicinal Plants extracted for screening against COVID-19 Main Protease. The compounds were further screened using Pyrex virtual screening tool and then best inhibitors, top 19 compounds optimally docked to the COVID-19 Main Protease structure to understand the participation of specific amino acids with inhibitors at active sites. Total 19 best compounds were identified after screening based on their highest binding affinity with respect to the other screened compounds. Out of 19, 6 best compounds were further screened based on their binding affinity and best ADME properties. Nelfinavir exhibited highest binding energy -8.4 kcal/mol and strong stability with the TRP207, ILE281, LEU282, PHE3, PHE291, GLN127, ARG4, GLY283, GLU288, LYS5, LYS137, TYR126, GLY138, TYR126, SER139 and VAL135 amino acid residues of COVID-19 Main Protease participating in the interaction at the binding pocket. In addition to Nelfinavir (-8.4), Rhein (-8.1), Withanolide D (-7.8), Withaferin A (-7.7), Enoxacin (-7.4), and Aloe-emodin (-7.4) also showed good binding affinity and best ADME properties. Our findings suggest that these compounds can be used as potential inhibitors against COVID-19 Main Protease, which could be helpful in inhibiting the propagation of the Novel Coronavirus (COVID-19). Moreover, further in vitro and in vivo validation of these findings would be very helpful to bring these inhibitors to next level study.

Identification of phytochemical inhibitors against main protease of COVID-19 using molecular modeling approaches

“…Besides the uses of various FDA-approved antiviral compounds as mentioned above, there are many in-silico studies have been performed to screen the novel phytochemical molecules as a potential inhibitors of main protease of SARS-CoV-2 or develop new drugs against COVID-19 (Khan et al, 2020;Khaerunnisa et al, 2020;Qamar et al, 2020;Gonzalez-Paz et al, 2020;Sharma & Kaur, 2020;Chandel et al, 2020;Adem et al, 2020;Gentile et al, 2020;Sun et al, 2020). But there is not a single report available for the function of phytochemicals namely, ursolic acid, carvacrol and oleanolic acid derived from the antiviral herbs for the treatment of COVID-19.…”

Theoretical Molecular Docking Study of the Structural Disruption of the Viral 3CL-Protease of COVID19 Induced by Binding of Capsaicin, Piperine and Curcumin Part 1: A Comparative Study with Chloroquine and Hydrochloroquine Two Antimalaric Drugs

“…This despite the fact that its safety has been questioned and severe adverse effects have been reported Kaisari and Borruat, 2020). In this sense, various bioactive compounds of plant origin have also been in silico studied why could they be used as alternative medicines or to develop new drugs against COVID-19 with fewer adverse effects (Khaerunnisa et al, 2020;Qamar et al, 2020;Sharma and Kaur, 2020;Chandel et al,, 2020;Adem et al,, 2020;Gentile et al,, 2020;. But little has been reported on the use of the MolDock molecular docking algorithm for the 3CL-protease study (Adem et al,, 2020), in which the docking score function is an extension of the linear part potential (PLP) that includes new hydrogen bonds and electrostatic terms to improve coupling precision (Thomsen and Christensen, 2006;Wang, 2020).…”

Potential Drugs for Treating COVID-19 Infection

“…The other candidates for treating COVID-19 include saquinavir, indinavir, shikonin, ebselen, atazanavir, carfilzomib, tipranavir, fosamprenavir, cyclosporin A, presatovir, enzaplatovir, abacavir, carmofur, bortezomib, maribavir, raltegravir, elvitegravir, montelukast, deoxyrhapontin, polydatin, chalcone, disulfiram, tideglusib, PX-12, TDZD-8, and cinanserin (60)(61)(62)(63)(64). Imatinib, as an inhibitor of type II transmembrane serine protease (TM-SPSS2) and BCR-ABL kinase, inhibits the fusion of virions with the endosomal membrane (62,64). Furthermore, Chinese herbs including Rhizoma Polygoni Cuspidati and Radix Sophorae Tonkinensis possibly have active ingredients that may be efficient against COVID-19 (65-67).…”