Drug repositioning to target NSP15 protein on SARS-CoV-2 as possible COVID-19 treatment - PubMed (original) (raw)

. 2021 May 15;42(13):897-907.

doi: 10.1002/jcc.26512. Epub 2021 Mar 13.

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Drug repositioning to target NSP15 protein on SARS-CoV-2 as possible COVID-19 treatment

Yudibeth Sixto-López et al. J Comput Chem. 2021.

Abstract

SARS-CoV and SARS-CoV-2 belong to the subfamily Coronaviridae and infect humans, they are constituted by four structural proteins: Spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N), and nonstructural proteins, such as Nsp15 protein which is exclusively present on nidoviruses and is absent in other RNA viruses, making it an ideal target in the field of drug design. A virtual screening strategy to search for potential drugs was proposed, using molecular docking to explore a library of approved drugs available in the DrugBank database in order to identify possible NSP15 inhibitors to treat Covid19 disease. We found from the docking analysis that the antiviral drugs: Paritaprevir and Elbasvir, currently both approved for hepatitis C treatment which showed some of the lowest free binding energy values were considered as repositioning drugs to combat SARS-CoV-2. Furthermore, molecular dynamics simulations of the Apo and Holo-Nsp15 systems were performed in order to get insights about the stability of these protein-ligand complexes.

Keywords: COVID-19; Elbasvir; Nsp15; Paritaprevir; SARS-CoV-2; molecular dynamic simulation.

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Figures

SCHEME 1

SCHEME 1

Elbasvir and Paritaprevir, drugs proposed with possible activity against Nsp15 of SARS‐CoV‐2, obtained by virtual screening approach

FIGURE 1

FIGURE 1

Binding poses of the 16 compounds selected by virtual screening obtained by molecular docking simulations against Nsp15 of SARS‐CoV‐2. (A) Difenoxine and Levocabastine (shown in color light pink and cyan, respectively), (B) Digoxin, Deslanoside, Acetyldigitoxin, Digitoxin (shown in color yellow‐orange, marine, violet purple and yellow, respectively), (C) Elbasvir (shown in color wheat), (D) Ergotamine and dyhydroergotamine (shown in magenta and gray, respectively), (E) Ivosidenib and entrectinib (shown in color deepteal and tvgreen, respectively), (F) Paritaprevir (slate color), (G) Atavaquone, Bedaquiline, Sibutramine (shown in magenta, gray and olive color, respectively), (H) irinotecan (shown in wheat color), (I) Nsp15 and close up of the catalytic site. Nsp15 are depicted as green cartoon and residues belonging to catalytic site as orange ball and stick, ligands are depicted as stick

FIGURE 2

FIGURE 2

Interactions observed between ligands and NSP15 of SARS‐CoV‐2 obtained by molecular docking. (A) Acetyldigitoxin, (B) Atavaquone, (C) Bedaquiline, (D) Digitoxin, (E) Difenoxin, (F) Deslanosido, (G) Digoxin, (H) Dihydroergotamine, (I) Elbasvir, (J) Ergotamine, (K) Entrectinib, (L) Ivodesinib, (M) Irinotecan, (N) Levocabastin, (O) Paritaprevir, (P) Sibutramine. Interactions are color coded as indicated at the right bottom of the figure, that was built using discovery studio V1626

FIGURE 3

FIGURE 3

Geometrical parameters of 30 ns MD simulations. Carbon alpha atoms were considered for the calculations employing GROMACS program. (A) RMSD and (B) RMSF. Apo Nsp15 is depicted as black lines, while complex Nsp15‐Elbasvir is depicted in red and Nsp15‐Paritaprevir is depicted as blue line

FIGURE 4

FIGURE 4

Most populated cluster conformation retrieved from the MD simulation. (A) Apo Nsp15, (B) Nsp15‐Elbasvir, (C) Nsp15‐Paritaprevir and (D) Nsp15‐citrate. In panel A native Nsp15 is overlapped with most populated cluster conformation of apo Nsp15. Native Nsp15 is depicted as cyan ribbon, while most populated cluster conformation of each system is depicted as green ribbon. Ligands are depicted as cyan ball and stick and the residues with which ligands interacted are depicted as orange sticks

FIGURE 5

FIGURE 5

Principal component analysis of apo‐Nsp15 and holo trajectories. (A) The first 20 eigenvectors of the covariance matrix, (B) Percentage of each eigenvectors vs eigenvalues, only the first 20 eigenvectors are depicted, (C) projection of the motion in the phase space along the first and second eigenvectors (PC2 vs. PC1) of the apo Nsp15, (D) projection of the motion in the phase space along the first and second eigenvectors (PC2 vs. PC1) of the complex Nsp15‐Elbasvir, (E) projection of the motion in the phase space along the first and second eigenvectors (PC2 vs. PC1) of the complex Nsp15‐Paritaprevir, (F) projection of the motion in the phase space along the first and second eigenvectors (PC2 vs. PC1) of the complex Nsp15‐citrate. Nsp15 are depicted in black, Nsp15‐Elbasvir in red, Nsp15‐Paritaprevir in green and Nsp15‐citrate in purple

FIGURE 6

FIGURE 6

Graphical representation of the two extreme projections. Representation of the two extreme projections along the first eigen vector of MD simulation of (A) apo Nsp15, (B) Nsp‐Elbasvir, (C) Nsp15‐Paritaprevir, and (D) Nsp15‐citrate

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