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Innovative Medicines & Omics Promising molecule against SARS-CoV-2 nucleocapsid

1. Introduction is worth noting that our research group previously used
in silico techniques to search for new drugs for SARS-
The coronavirus disease 2019 (COVID-19) pandemic, caused CoV-2 proteins, achieving positive results from compounds
by the rapid spread of the severe acute respiratory syndrome derived from natural products. 11,12
coronavirus 2 (SARS-CoV-2) worldwide, has resulted
in approximately seven million fatalities and triggering In the present study, a total of 20,115 compounds from
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extensive preventive measures globally. The SARS-CoV-2 the BindingDB database were subjected to virtual screening
is an RNA virus that presents varied clinical manifestations, against the nucleocapsid protein of the SARS-CoV-2 virus,
primarily impacting the respiratory system and often leading specifically targeting the C-terminal Domain (CTD).
to pneumonia. However, due to viral mutations, its symptoms The primary objective was to identify new compounds
can vary significantly among individuals and populations. 2 with potential activity against the nucleocapsid protein
through drug repositioning and bioisosterism techniques.
The first cases of this new pneumonia were identified in
Wuhan, China, in late 2019, marking the onset of urgent These compounds should exhibit ideal pharmacokinetic
international mobilization in public health. A race for and pharmacodynamic characteristics. This approach
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solutions began, with the genomic sequencing of the virus aims to develop more effective and specific treatments for
shared by China with the World Health Organization and COVID-19, optimizing the use of available resources.
other countries in January 2020 as an initial milestone. This 2. Materials and methods
milestone sparked a new push to understand and contain
the disease, with vaccines as initial targets. 2 2.1. Acquisition and preparation of the target
protein and ligands
A detailed understanding of the virus’s structure and
function has become crucial for developing effective The N-CTD of the nucleocapsid protein (N protein) of the
control and treatment strategies. Therapeutic strategies SARS-CoV-2 virus was retrieved from the Protein Data
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have been oriented toward essential molecular targets Bank (PDB) server under the code 6WZQ and prepared
of SARS-CoV-2, such as the spike (S) protein (which using the MGLTools software. All co-crystallized ligands
mediates the virus’s entry into host cells), the 3CLpro and water molecules were removed. In addition, missing
and PLpro proteases (crucial for viral replication), the hydrogens and Koolman charges were added. Finally, the
RNA-dependent RNA polymerase (RdRp; vital for Gridbox was defined in the central cleft of the tetramer to
replication of the viral genome), and the helicase (nsp13; encompass the amino acids reported in the protein’s base
for replication and transcription of the viral genome). article deposited in the PDB. The coordinates were thus
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In addition to the previously mentioned targets, there is defined as Center X: −8.048, Center Y: 5.966, Center Z:
another important but less explored therapeutic target: the 22.445, Size X: 23.25, Size Y: 23.25, and Size Z: 21.0. The
nucleocapsid protein (N). This protein plays a crucial role compounds library was obtained from the BindingDB
in replication, virion assembly, transcription regulation, server, totaling 20,115 compounds. All compounds were
and viral genome replication. It is highly relevant because prepared using the OpenBabel software, with protonation
it is highly conserved across different coronavirus strains. at pH 7.0 and the generation of 3D coordinates.
This means that it is less likely to mutate compared to other
viral proteins, and therefore, there is a lower probability of 2.2. High-throughput virtual screening
developing resistance to a particular drug. 4-6 The 20,115 compounds were docked to the N-CTD (PDB
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An effective approach to developing new strategies ID: 6WZQ) protein using the Autodock Vina software,
is through in silico techniques. According to the following the methodology employed by our research
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International Federation of Pharmaceutical Manufacturers group. 11,12 The binding energy results were arranged in
and Associations, reverse pharmacology holds significant descending order, placing the compounds with the lowest
potential in developing new drugs. The traditional drug binding energy at the top. Subsequently, a 3D analysis of
discovery process, which includes identifying a potential the results was carried out using the Pymol software. The
compound, bioprospecting, preparation, testing, patenting, 2D diagram, which shows the types of interactions between
and commercialization, typically costs around $1.3 billion the selected ligands and the target protein, was generated
and takes between 10 and 15 years to complete. 8-10 Conversely, using Ligplot+ software. 16
the application of bioinformatics methodologies such as 2.3. Absorption, distribution, metabolism,
computer-aided drug design to reverse pharmacology can
lead to a reduction of approximately 50% in the cost and excretion, and toxicity (ADME-Tox) analyses
production time of the drug, in addition to the clear benefit The selected compounds were analyzed for their
of decreasing the number of laboratory animal tests. It pharmacodynamic and pharmacokinetic properties,
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Volume 1 Issue 1 (2024) 116 doi: 10.36922/imo.3731