Evaluation of the potency of FDA-approved drugs on wild type and mutant SARS-CoV-2 helicase (Nsp13)

Abstract

SARS-CoV-2 has caused COVID-19 outbreak with nearly 2 M infected people and over 100K death worldwide, until middle of April 2020. There is no confirmed drug for the treatment of COVID-19 yet. As the disease spread fast and threaten human life, repositioning of FDA approved drugs may provide fast options for treatment. In this aspect, structure-based drug design could be applied as a powerful approach in distinguishing the viral drug target regions from the host. Evaluation of variations in SARS-CoV-2 genome may ease finding specific drug targets in the viral genome. In this study, 3458 SARS-CoV-2 genome sequences isolated from all around the world were analyzed. Incidence of C17747T and A17858G mutations were observed to be much higher than others and they were on Nsp13, a vital enzyme of SARS-CoV-2. Effect of these mutations was evaluated on protein-drug interactions using in silico methods. The most potent drugs were found to interact with the key and neighbor residues of the active site responsible from ATP hydrolysis. As result, cangrelor, fludarabine, folic acid and polydatin were determined to be the most potent drugs which have potency to inhibit both the wild type and mutant SARS-CoV-2 helicase. Clinical data supporting these findings would be important towards overcoming COVID-19.

Keywords: Drug repositioning; Helicase; Mutation analysis; Nsp13; SARS-CoV-2.

Fig. 1

Alignment of helicase amino acid sequences from four isolates of SARS-CoV-2; Wild Type: Wuhan-Hu-1 and mutant: USA/WA6-UW3/human/2020.

Fig. 2

a) Root-mean-square deviations (RMSDs) and b) fluctuations (bfactor) of the Cα backbone carbon atoms for mutant (green) and wild type (red) SARS-CoV-2 helicases of MD simulation during 50 ns.

Fig. 3

Superimpositions of mutant (green) and wild type (white) SARS-CoV-2 helicases after MD simulation. The representation in the hexagon is the ATP-binding site and the active residues are shown in yellow, two mutations (P504L and Y541C) are shown in red.

Fig. 4

Calculation of distances between domains after MD simulation. a) SARS-CoV-2 wild type helicase b) SARS-CoV-2 mutant (P504L and Y541C) helicase.

Fig. 5

Molecular docking views of drugs in the ATP-binding site of wild type SARS-CoV-2 helicase. (a) Surface (right) and cartoon (left) views of all poses in the cleft. (b) Fludarabine, (c) cangrelor, (d) polydatin, (e) folic acid.

Fig. 6

Molecular docking views of drugs in the ATP-binding site of mutant SARS-CoV2 helicase. (a) Surface (right) and cartoon (left) views of the all poses in the cleft. (b) Fludarabine, (c) cangrelor, (d) polydatin, (e) folic acid.

Supplement Fig. 1

Align. of SARS-CoV 2 nuc. seq. from 3458 isolates (region 17701-17900 on ref. genome).