posted on 2021-02-19, 18:34authored byKartikay Prasad, Shahzaib Ahamad, Hema Kanipakam, Dinesh Gupta, Vijay Kumar
The
COVID-19 pandemic caused by SARS-CoV-2 represents a global
public health emergency. The entry of SARS-CoV-2 into host cells requires
the activation of its spike protein by host cell proteases. The serine
protease, TMPRSS2, and cysteine proteases, Cathepsins B/L, activate
spike protein and enable SARS-CoV-2 entry to the host cell through
two completely different and independent pathways. Therefore, inhibiting
either TMPRSS2 or cathepsin B/L may not sufficiently block the virus
entry. We here hypothesized that simultaneous targeting of both the
entry pathways would be more efficient to block the virus entry rather
than targeting the entry pathways individually. To this end, we utilized
the network-based drug repurposing analyses to identify the possible
common drugs that can target both the entry pathways. This study,
for the first time, reports the molecules like cyclosporine, calcitriol,
and estradiol as candidate drugs with the binding ability to the host
proteases, TMPRSS2, and cathepsin B/L. Next, we analyzed drug–gene
and gene–gene interaction networks using 332 human targets
of SARS-CoV-2 proteins. The network results indicate that, out of
332 human proteins, cyclosporine interacts with 216 (65%) proteins.
Furthermore, we performed molecular docking and all-atom molecular
dynamics (MD) simulations to explore the binding of drug with TMPRSS2
and cathepsin L. The molecular docking and MD simulation results showed
strong and stable binding of cyclosporine A (CsA) with TMPRSS2 and
CTSL genes. The above results indicate cyclosporine as a potential
drug molecule, as apart from interacting with SARS-CoV-2 entry receptors,
it also interacts with most of SARS-CoV-2 target host genes; thus
it could potentially interfere with functions of SARS-CoV-2 proteins
in human cells. We here also suggest that these antiviral drugs alone
or in combination can simultaneously target both the entry pathways
and thus can be considered as a potential treatment option for COVID-19.