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\title{Repurposing of FDA-approved Drugs against Active Site and Potential
Allosteric Drug Binding Sites of COVID-19 Main Protease}



\author[1]{Merve Yuce}%
\author[1]{Erdem Cicek}%
\author[1]{Tuğçe İnan}%
\author[2]{Aslıhan Başak Dağ}%
\author[1]{Özge  Kürkçüoğlu}%
\author[1]{Fethiye Aylin Sungur}%
\affil[1]{Istanbul Technical University}%
\affil[2]{Istanbul Technical University Faculty of Science and Letters}%


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  \date{June 10, 2024}


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\begin{abstract}
The novel coronavirus disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious
negative effects on health, social life, and economics. Recently,
vaccines from various companies have been urgently approved to control
SARS-CoV-2 infections. However, any specific antiviral drug has not been
confirmed so far for regular treatment. An important target is the main
protease (Mpro), which plays a major role in replication of the virus.
In this study, Gaussian and residue network models are employed to
reveal two distinct potential allosteric sites on Mpro that can be
evaluated as drug targets besides the active site. Then, FDA-approved
drugs are docked to three distinct sites with flexible docking using
AutoDock Vina to identify potential drug candidates. 14 best molecule
hits for the active site of Mpro are determined. 6 of these also exhibit
high docking scores for the potential allosteric regions. Full-atom
molecular dynamics simulations with MM-GBSA method indicate that
compounds docked to active and potential allosteric sites form stable
interactions with high binding free energy ([?]Gbind) values. [?]Gbind
values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for
the potential allosteric site 1, and -42.93 kcal/mol for the potential
allosteric site 2. Energy decomposition calculations per residue
elucidate key binding residues stabilizing the ligands that can further
serve to design pharmacophores. This systematic and efficient
computational analysis successfully determines ivermectine, diosmin and
selinexor currently subjected to clinical trials, and further proposes
bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated
against SARS-CoV-2 infection%
\end{abstract}%



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