Quinolines-Based SARS-CoV-2 3CLpro and RdRp Inhibitors and Spike-RBD-ACE2 Inhibitor for Drug-Repurposing Against COVID-19: An in silico Analysis

Abstract

The novel coronavirus SARS-CoV-2 disease "COVID-19" emerged in China and rapidly spread to other countries; due to its rapid worldwide spread, the WHO has declared this as a global emergency. As there is no specific treatment prescribed to treat COVID-19, the seeking of suitable therapeutics among existing drugs seems valuable. The structure availability of coronavirus macromolecules has encouraged the finding of conceivable anti-SARS-CoV-2 therapeutics through in silico analysis. The results reveal that quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI) and saquinavir strongly interact with the active site (Cys-His catalytic dyad), thereby are predicted to hinder the activity of SARS-CoV-2 3CLpro. Out of 113 quinoline-drugs, elvitegravir and oxolinic acid are able to interact with the NTP entry-channel and thus interfere with the RNA-directed 5'-3' polymerase activity of SARS-CoV-2 RdRp. The bioactivity-prediction results also validate the outcome of the docking study. Moreover, as SARS-CoV-2 Spike-glycoprotein uses human ACE2-receptor for viral entry, targeting the Spike-RBD-ACE2 has been viewed as a promising strategy to control the infection. The result shows rilapladib is the only quinoline that can interrupt the Spike-RBD-ACE2 complex. In conclusion, owing to their ability to target functional macromolecules of SARS-CoV-2, along with positive ADMET properties, quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI), saquinavir, elvitegravir, oxolinic acid, and rilapladib are suggested for the treatment of COVID-19.

Keywords: RNA-dependent RNA-polymerase; SARS-CoV-2; drug repurposing; main-protease (3CLpro); quinoline based-drugs; spike-ACE2 complex.

Figure 1

(A) The 3CLpro monomer has three domains, namely domain I (residues 8–101), domain II (residues 102–184), and domain III (residues 201–303). The red arrow mark indicates the region of the active site of 3CLpro, which is located in the gap between domains I and II, and has a CysHis catalytic dyad (Cys145 and His41). (B,C) Depicts the binding region of the quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI) (−6.8 Kcal/mol) and saquinavir (−8.5 Kcal/mol) with SARS-CoV-2 3CLpro, respectively. (D,E) Shows the super-position view of the binding sites and their interacting amino acids of quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI) and saquinavir with SARS-CoV-2 3CLpro, respectively. (F,H) Indicates the interaction with the active catalytic dyad of SARS-CoV-2 3CLpro (Cys145 and His41). (G) Hydrogen bond formation of quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI) with Glu166 residues of 3CLpro at 2.044 Å distance. (I,J) Reveal the interacted aminoacid residues of SARS-CoV-2 3CLpro with quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI) and saquinavir.

Figure 2

The binding patterns and aminoacid interactions of the best scoring quinolines with SARS-CoV-2 3CLpro. The red circle-marking indicates the interaction with the active site of SARS-CoV-2 3CLpro (CysHis catalytic dyad).

Figure 3

The binding patterns and aminoacid interactions of the best scoring quinolines with SARS-CoV-2 RdRp. The red circle-marking indicates the interaction with the NTP entry channel of SARS-CoV-2.

Figure 4

(A,B) Shows the binding region and close-up view of the interacting amino acids of elvitegravir (−7.1 Kcal/mol) with SARS-CoV-2 RdRp, respectively. (C,D) Individually depicts the binding region and super-position view of the interacting amino acids of oxolinic acid (−7.1 Kcal/mol) with SARS-CoV-2 RdRp, respectively. (E,G) Visualizes the interaction with the NTP entry channel of SARS-CoV-2 RdRp (a set of hydrophilic residues such as Lys545, Arg553, and Arg555) of elvitegravir and oxolinic acid. (F,H) Shows the hydrogen bond formation of elvitegravir (Lys621 with a distance of 1.931 Å) and oxolinic acid (Thy456, Ser682, and Arg624 with a distance of 1.224, 1.815, and 2.904 Å, respectively). (I,J) Illustrate the interacted aminoacid residues of SARS-CoV-2 3CLpro with elvitegravir and oxolinic acid.

Figure 5

The binding patterns and aminoacid interactions of the top ten scoring quinolines with the RBD interface of the Spike-ACE2 complex. The red circle-marking indicates the interaction with the RBD interface of Spike-ACE2 complex.

Figure 6

(A) Shows the receptor binding domain (RBD) of SARS-CoV-2 Spike protein with human ACE-2 receptor for viral entry into host cells. (B) The interrupting mode of rilapladib (−9.7 Kcal/mol) on the interface of RBD of the Spike protein-ACE2 complex. (C) Super-position view of the binding interations of rilapladib on the interface of RBD of the Spike protein-ACE2 complex. (D) Shows the interacted aminoacid residues of rilapladib on the interface of RBD of the Spike protein-ACE2 complex.