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.

A survey on computational methods in discovering protein inhibitors of SARS-CoV-2

“…This process revealed the unique blueprint of SARS-CoV-2 M pro , leading to a definition of a pharmacophore based on the specific structure, which provides a strong foundation for rational drug design for SARS-CoV-2 M pro . Ugurel et al [ 153 ] analyzed 3458 SARS-CoV-2 genome sequences isolated from 58 countries. They found the incidence of C17747T and A17858G mutations on helicase (NSP13) were significantly higher than others.…”

Application of omics technology to combat the COVID‐19 pandemic

“…By now, silent mutation and composition‐related mutations are identified in the RdRp gene of SARS‐CoV‐2, arisen a risk on possible drug‐resistance to clinical used RdRp‐targeted drugs 92 . Moreover, studies have reported mutations in methyltransferase complex (Nsp10–Nsp16) and helicase (Nsp13) of SARS‐CoV‐2, which can facilitate host–pathogen interaction 93,94 . Membrane (M) protein participates many virus–cell interactions.…”

“… 92 Moreover, studies have reported mutations in methyltransferase complex (Nsp10–Nsp16) and helicase (Nsp13) of SARS‐CoV‐2, which can facilitate host–pathogen interaction. 93 , 94 Membrane (M) protein participates many virus–cell interactions. M: I82T and V70L mutations, which located in the glucose transport region of M protein, can enhance the uptake of glucose during viral replication, and these mutations will be resulted in SARS‐CoV‐2 infection in younger people.…”

The SARS-CoV-2 helicase as a target for antiviral therapy: Identification of potential small molecule inhibitors by in silico modelling

“…The first open reading frame (ORF1a/b) of the SARS-CoV-2 RNA genome encodes for 16 non-structural proteins, while the remaining ORFs encode for structural and accessory proteins [ [10] , [11] , [12] ]. The non-structural proteins (nsps) have been found to assemble into a replication and transcription (RTC) complex that is essential for viral survival [ 4 , 13 ].…”