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

including ADME-Tox, using the pKCSM server. Intestinal 3.2. In silico ADME-Tox evaluation of the top five
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absorption values were assessed, with results above 30% candidate compounds from high-throughput
considered good absorption. The volume of distribution screening virtual
at steady state (VDSS) was evaluated, with results below The ADME-Tox results have shown that compound
−0.15 being considered better distribution in plasma than BDBM6732 had an excellent human intestinal absorption
in tissue and above 0.45 being considered the opposite. (HIA) of 99.53%, a moderate VDSS of −0.672, positive
Total clearance, AMES toxicity, maximum tolerated dose results in the AMES test indicating genotoxic potential,
(MTD), and hepatotoxicity were also evaluated. a positive MTD of 0.463 and hepatotoxicity. Conversely,
2.4. Bioisosterism compound BDBM9614 displayed a lower HIA of 55.42%,
a slightly lower VDSS of −0.603, negative results in the
When compounds showed predictions of any side effects AMES test suggesting lower genotoxicity, a negative MTD
in the ADME-Tox tests, they underwent a bioisosterism of −0.234, and hepatotoxicity. Compound BDBM15149,
process in the MB-Isoster software. Portions of the on the other hand, exhibited a high HIA of 92.06%, a
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compounds were modified by others that did not alter favorable VDSS of −0.099, positive results in the AMES test
the physicochemical characteristics of the compound but indicating genotoxic potential, a positive MTD of 0.391,
eliminated the predictions of undesired side effects. After and hepatotoxicity. Compound BDBM15179 displayed a
the modifications, the compounds were docked to the good HIA of 88.35%, a reasonable VDSS of −0.199, negative
protein again. results in the AMES test suggesting lower genotoxicity,

3. Results a positive MTD of 0.431, and no hepatotoxicity. Finally,
Compound BDBM7088 showed a moderate HIA of
3.1. Virtual screening 73.48%, a nearly neutral VDSS of −0.015, negative results
First, a PDB search was conducted to identify this in the AMES test indicating lower genotoxicity, a positive
study’s target protein. The protein under the code MTD of 0.438, and no hepatotoxicity (Table 2).
6WZQ, determined by X-ray diffraction methodology Overall, compound BDBM6732 exhibited better
with a resolution of 1.45 Å, was selected. Then, 20,115 ADME-Tox properties despite showing positive results
compounds were evaluated for their bonding capability to for genotoxic potential and hepatotoxicity because the
protein 6WZQ. The top five compounds with the lowest overall assessment of ADME-Tox properties involves a
binding energy results were selected and are detailed in combination of various factors.
Table 1. The binding modes and interactions between the
nucleocapsid protein’s N-CTD and all ligands from Table 1 3.3. Bioisosterism for BDBM6732 compound
are illustrated in Figure S1. The compounds exhibited The software Mb-Isoster identified 225 possible
binding energy ranging from −13.4 to −11.0 kcal/mol. modifications for the compound BDBM6732. Following
The compound BDBM6732 exhibited the lowest binding this, molecular docking simulations were conducted to
energy at the active site of the nucleocapsid protein of evaluate the binding capacity of analogs generated in the
SARS-CoV-2, establishing three hydrogen bonds (Ser327 same region of the 6WZQ protein, which was earlier used
[A] and Thr334 [B] [2x]) and 12 hydrophobic contacts in the virtual screening stage. The top five compounds
(Gln281 [A], Thr282 [A], Glu323 [A], Thr325 [A], (Figure S2) with the lowest binding energy results were
Trp330 [A], Thr332 [A], Gly335 [B], Ala336 [B], Glu280 selected and are detailed in Table 3. The binding modes
[D], Gln 281 [D], Thr282 [D], Gln283 [D]) (Figure 1B). and interactions between the nucleocapsid protein’s
After analyzing the top five compounds, we observed N-CTD and all ligands from Table 3 are illustrated in
that BDBM7088 exhibits a greater number of hydrogen Figure S3. The compounds exhibited binding energy
bonds and a lesser number of hydrophobic interactions. ranging from −14.1 to −12.2 kcal/mol. BDBM6732-bio2
However, this compound’s estimated binding energy was exhibited the lowest binding energy when binding to the
weaker than other compounds. In addition, our findings 6WZQ protein, establishing one hydrogen bond (Thr332
suggest that no hot spots or key residues significantly [A]) and nine hydrophobic contacts (Thr282 [A], Glu323
contribute to establishing hydrogen bond interactions with [A], Thr325 [A], Trp330 [A], Thr334 [A], Thr334 [B],
the top five compounds. Nonetheless, when examining the Ala336 [B], Arg276 [D] and Gln 283) (Table 3). The
hydrophobic interactions, our results suggest that Gln281 compound BDBM6732-bio1 exhibited one hydrogen
(A), Gu323 (A), Thr 325 (A), Thr330 (A), Thr332 (A), bond (Thr334 [B]) and 14 hydrophobic contacts (Thr282
Gly335 (B), Ala336 (B), and Gln283 (C) may behave as hot [A], Glu323 [A], Thr325 [A], Pro326 [A], Ser327 [A],
spot residues (Table 1). Trp330 [A], Thr332 [A], Gly335 [B], Ala 336 [B], Arg276

Volume 1 Issue 1 (2024) 117 doi: 10.36922/imo.3731