Page 127 - IMO-1-1

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

and negative AMES test results. Compound BDBM6732- Administration (FDA) approved small molecules indicated
bio2 has an excellent HIA of 100% and a low VDSS of that ceftriaxone (an antibiotic) and lopinavir (an antiviral)
−0.877, with a high TR of 0.546 and negative AMES test exhibit more favorable binding affinity to the C-terminal
results. Compound BDBM6732-bio3 has a high HIA of region of the N protein compared to other compounds.
99.6% and a moderate VDSS of −1.102, with a TR of 0.487 A molecular docking simulation has been performed
and negative AMES test results. Compound BDBM6732- using the 6WZQ protein and two ligands (ceftriaxone and
bio4 has a lower HIA of 97.36% and a moderate VDSS of lopinavir) for comparative purposes with our results. The
−1.377, with a lower TR of 0.325 and negative AMES test same parameters and ligand binding region in the protein
results. Compound BDBM6732-bio5 has a perfect HIA used in our study were employed. The results have revealed an
of 100%, a low VDSS of −0.897, and a TR of 0.494, with estimated binding energy of −9.4 kcal/mol for ceftriaxone and
negative AMES test results. Compound BDBM6732-bio2 −9.2 kcal/mol for lopinavir. This affinity estimate is lower than
has the most favorable ADME-Tox descriptors, followed the values of −13.4 kcal/mol, −14.1 kcal/mol, and −13.9 kcal/
by compounds BDBM6732-bio5, BDBM6732-bio1, and mol obtained for the compounds BDBM6732, BDBM6732-
BDBM6732-bio3 (Figure 1A and Table 4). bio2, and BDBM6732-bio1, respectively. Consequently, it is
suggested that the analogs proposed in this work are more
4. Discussion promising than the compounds referenced in that study.

20
The current study employed the N-CTD of the N protein of In another study, a virtual screening simulation involving
the SARS-CoV-2 virus, under the code 6WZQ, for the virtual 2456 FDA-approved small molecules has indicated that the
screening of potential drug candidates. Our main goal was compounds Cefoperazone (an antibiotic) and Ceftaroline
to discover new compounds that could effectively hinder fosamil (an antibiotic) have the potential to act as inhibitors
the replication and progression of the virus by inhibiting the of the C-terminal region of the N protein. To compare our
N-CTD. After identifying a promising candidate molecule findings, a molecular docking simulation has been executed
through computational screening, we used bioisosterism using the 6WZQ protein and two ligands (cefoperazone and
to design a series of similar compounds with improved ceftaroline fosamil). The same parameters and ligand binding
binding affinity for the N-CTD. Our computational analyses region in the protein used in our study were employed. The
revealed two potential analogs with higher predicted outcomes have demonstrated an estimated binding energy
affinities compared to the original compound, indicating of −10.0 kcal/mol for cefoperazone and −9.2 kcal/mol for
their potential as more effective therapeutic agents. These ceftaroline fosamil. These affinity estimates are lower than
findings lay the groundwork for further experimental the obtained values for the compounds selected by virtual
validation and development of new antiviral drugs targeting screening and all proposed analogs.
the SARS-CoV-2’s N protein, providing alternative treatment In a subsequent literature search, we identified two
options beyond current clinical compounds. potential compounds— suramin (antiparasitic) and
21
The N-CTD of the SARS-CoV-2’s N protein plays a vital chicoric acid (antioxidant, anti-inflammatory, and
role in viral replication and assembly, making it a crucial immunomodulatory), which possess in vitro inhibitory
22
target for antiviral drug development. Inhibiting N-CTD activities of N-CTD. These compounds were then obtained
with therapeutic molecules can disrupt viral replication from the PubChem server, transferred to the local server,
and genome packaging, presenting a potent strategy to and docked to N-CTD using the same parameters
combat COVID-19. Some studies have employed a drug employed in the simulations presented in our study.
5
repositioning strategy to readily address emerging health Suramin exhibited relative binding energy comparable to
threats. 19,20 In one specific study, a virtual screening that of BDBM6732 (−13.3 kcal/mol for suramin compared
19
simulation of 3142 clinical-stage or U.S. Food and Drug to −13.4 kcal/mol for BDBM6732), which is lower than the
Table 4. In silico ADME ‑ Tox evaluation of the five candidate analogs compounds proposed from the compound BDBM6732

BindingDB identifier HIA (%) VDSS (log) TR (ml/min/kg) AMES MTD (mg/kg/dia) Hepatotoxicity
BDBM6732-bio1 98.74 −1.363 0.452 No 0.388 No
BDBM6732-bio2 100.00 −0.877 0.546 No 0.440 No
BDBM6732-bio3 99.60 −1.102 0.487 No 0.434 No
BDBM6732-bio4 97.36 −1.377 0.325 No 0.376 No
BDBM6732-bio5 100.00 −0.897 0.494 No 0.426 No
Abbreviations: AMES: AMES toxicity test (mutagenesis); HIA: Human intestinal absorption; MTD: Maximum tolerated dose; TR: Total release;
VDSS: Volume of distribution at steady state.

Volume 1 Issue 1 (2024) 121 doi: 10.36922/imo.3731