Page 105 - ITPS-7-2

INNOSC Theranostics and
Pharmacological Sciences Molecular docking against SARS-CoV-2

entering the host cell, the virus releases its RNA genome, 2. Methods
which undergoes transcription through protein cleavage
and assembly of the replicase-transcriptase complex. Viral An exhaustive search was conducted across scientific
RNA replication occurs, and structural viral proteins are databases and publications such as PubMed, Google
synthesized, assembled, and packaged within host cell Scholar, FEBS Press, Springer Link, and Nature to identify
membranes before virions release. 5,6 literature pertaining to chemical compounds or drugs
capable of interacting with the SARS-CoV-2 S-glycoprotein.
Understanding the variability of the S-glycoprotein The A chain of the S-glycoprotein (6VSB, EM Map
is necessary for developing new vaccines, guaranteeing EMD-21375) was chosen using the UCSF Chimera
15
specificity, broad reactivity, and persistent immunity Software v.1.16 developed by the University of California.
16
through cross-reactive responses. Any change in the Using the Swiss-Model server provided by Biozentrum,
7
receptor binding domain (RBD) region of the spike University of Basel, homology modeling of the protein
17
protein can impact its binding affinity, necessitating structures was carried out to predict the missing structures
close monitoring of mutant strains. Molecular docking in the protein and complete it. Subsequently, the Protox-II
studies of the spike virus and the ACE2 receptor junction server provided by the Charité Universita Medizin Berlin
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are often utilized to assess potential changes in binding filtered out innocuous compounds by applying a score
affinity. However, a comprehensive understanding of greater than four on the toxicity scale. Following this,
8
S-glycoprotein binding does not equate to knowledge of its the 3D molecular representation of the glycoprotein with
pharmacological interactions. 6VSB identification was downloaded in PDB format from
The pandemic underscores the critical need for the Protein Data Bank provided by the National Centre
19
effective medicines to prevent and treat viral infections, for Biotechnology Information, and it was subjected to
driving the urgency for the development of new cleaning and preparation for further analysis.
treatments. However, given that the drug development To prepare and simulate ligand docking, we used the
process is both lengthy and costly, in silico evaluation software PyRx v.0.8 developed by Sargis Dallakyan. This
20
through molecular simulation docking is employed to software enabled us to obtain the binding free energy
expedite this process. (∆G) of the compounds and identify the most promising
At present, therapeutic options for COVID-19 are drugs. This modeling process involved 10 resampling steps
limited, primarily comprising antiviral medications such to obtain the statistical parameters necessary for grouping
as molnupiravir, nirmatrelvir + ritonavir (Paxlovid), and medications with the highest affinity. Subsequently, a cluster
remdesivir. In addition, monoclonal antibody therapies, analysis based on Euclidean distances was conducted using
exemplified by bamlanivimab/etesevimab and casirivimab/ Ward’s method. This grouping was achieved through
imdevimab, along with anti-inflammatory medications 1000 bootstrap–MCMC, facilitated by the Past v.4.2
such as dexamethasone and immunomodulatory agents program developed by Hammer. 21
such as baricitinib and tocilizumab, constitute available 3. Results
treatment options. These treatments have been made
available following clearance from the Food and Drug Forty-four drugs with therapeutic potential were identified
Administration (FDA). The majority have undergone within the consulted data sets. The binding affinity of
testing in cell cultures, with a few demonstrating these drugs ranges between −3.76 and −7.22 kcal mol ,
−1
promising results in clinical trials. 9-14 In this context, a drug as measured by their critical energy cost values (∆G). The
repositioning study has been carried out using in silico cytotoxicity predicted by the Protox-II assay ranges from 4
tools targeting the delta spike protein/ACE2 interface, to 6 toxicity points (Table 1).
employing a virtually screened library of 4388 approved Overall, the clustering analysis revealed two groups of
drugs. The results suggest that several antihistaminic drugs, with a high-affinity subgroup consisting of estradiol
drugs form stable complexes against the spike RBD (with benzoate, itraconazole, maraviroc, indinavir, vicriviroc,
binding affinities between −32.92 and −53.78 kcal mol ), dasabuvir, dolutegravir, and telaprevir (Figure 1). Within
−1
while practically all currently used antiviral drugs are not this high-affinity subgroup, estradiol benzoate and
included in Spike-Antihistamine interaction. 13 indinavir exhibited the lowest toxicity values. Hence, based
The primary objective of this study is to propose and on this study, they may be considered as the drugs with the
evaluate various antiviral drugs with potential therapeutic most significant therapeutic potential. On the other hand,
effects, selecting those most promising for treating docosanol and valaciclovir comprised the lowest affinity
COVID-19 through serial simulations of molecular subgroup. It is worth noting that while some low-affinity
docking and a Markovian approach. antiviral drugs were identified, they have proven effective

Volume 7 Issue 2 (2024) 2 doi: 10.36922/itps.1651