In silico prediction of SARS-CoV-2 main protease and polymerase inhibitors: 3D-Pharmacophore modelling

Abstract

The outbreak of the second severe acute respiratory syndrome coronavirus (SARS-CoV-2) known as COVID-19 has caused global concern. No effective vaccine or treatment to control the virus has been approved yet. Social distancing and precautionary protocols are still the only way to prevent person-to-person transmission. We hope to identify anti-COVID-19 activity of the existing drugs to overcome this pandemic as soon as possible. The present study used HEX and AutoDock Vina softwares to predict the affinity of about 100 medicinal structures toward the active site of 3-chymotrypsin-like protease (3Clpro) and RNA-dependent RNA polymerase (RdRp), separately. Afterwards, MOE software and the pharmacophore-derived query methodology were employed to determine the pharmacophore model of their inhibitors. Tegobuvir (19) and compound 45 showed the best binding affinity toward RdRp and 3Clpro of SARS-CoV-2 in silico, respectively. Tegobuvir -previously applied for hepatitis C virus- formed highly stable complex with uncommon binding pocket of RdRp (E total: -707.91 Kcal/mol) in silico. In addition to compound 45, tipranavir (28) and atazanavir (26) as FDA-approved HIV protease inhibitors were tightly interacted with the active site of SARS-CoV-2 main protease as well. Based on pharmacophore modelling, a good structural pattern for potent candidates against SARS-CoV-2 main enzymes is suggested. Re-tasking or taking inspiration from the structures of tegobuvir and tipranavir can be a proper approach toward coping with the COVID-19 in the shortest possible time and at the lowest cost.Communicated by Ramaswamy H. Sarma.

Keywords: RdRp; SARS-CoV-2; docking study; pharmacophore modelling; protease 3Clpro.

Graphical abstract

Figure 1.

The flowchart of the present in-silico study.

Figure 2.

The other binding sites for non-nucleoside RdRp inhibitors removed from the common RdRp binding pocket (shown by yellow circle).

Figure 3.

Docked pose of tegobuvir on the crystallographic structure of SARS-CoV-2 RdRp. (A) Tegobuvir (yellow, stick model) are accommodated at the uncommon catalytic site of RdRp. The common main residues are indicated with a blank surface. (B) Docked pose of tegobuvir (yellow, stick model) in interaction with main residues (gray, line model) in the uncommon binding pocket of SARS-CoV-2 RdRp.

Figure 4.

Docked pose of INX-08189 on crystallographic structure of SARS-CoV-2 RdRp. (A) INX-08189 with RdRp of SARS-CoV-2. (B) Overlaid complexes of sofosbuvir (red line), INX-08189 (green line) and remdesivir (blue line) in interaction with main residues in the common active site of RdRp.

Figure 5.

Docked pose of RG7128 (green, stick model) as the best nucleoside inhibitor in the common RdRp catalytic site.

Figure 6.

Docked figures of top 4 molecule candidates with 3Clpro active site of SARS-CoV-2. Here, compound 45, tipranavir (28), 44 and atazanavir (26) are shown in pink, light blue, yellow and navy blue stick model, respectively.

Figure 7.

Interaction profile of the best-docked poses of 3Clpro inhibitors. (A) Compound (45), (B) Tipranavir (28), (C) Compound (44) and (D) Atazanavir (26).

Figure 8.

Pharmacophoric maps of the SARS-CoV-2 inhibitors. (A) RdRp inhibitors (B) 3Clpro/Mpro inhibitors with their inter-feature distances. Orange: ring aromatic (RA), Green: Hydrophobic centroid (HY), Blue: H-bond acceptor (HBA), Violet: H-bond donor (HBD), Gray: H-bond donor/acceptor. (HBD/HBA).