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

analogs BDBM6732-bio2 (−14.1 kcal/mol) and BDBM6732- BDBM6732-bio1) and validating their activities through
bio1 (−13.9 kcal/mol). Following the compound, chicoric in vitro cellular activation assays for targeted compound
acid demonstrated an estimated binding energy of activity. In addition, the analogs can be tested in biological
−9.9 kcal/mol, which is lower than the values obtained models that replicate the manifestation of COVID-19
for the compounds selected by virtual screening and their symptoms similar to those observed in humans.
proposed analogs. Table 5 summarizes these results. In
addition, Figure S4 depicts the interactions between the Acknowledgments
N-CTD of the N protein and all ligands from Table 5. The authors acknowledge the financial support by the
The compound BDBM6732 functions as a cyclin- Brazilian agencies. This study was supported in part by
dependent protein kinase inhibitor and has the potential for the Coordenação de Aperfeiçoamento de Pessoal de Nível
antiproliferative activity in human carcinoma. However, Superior (CAPES) (Número da Bolsa/Prêmio: 001) and
23
the suggested analogs’ activity has not yet been documented Fundação de Amparo à Pesquisa do Estado de Minas
in the literature. In silico ADME-Tox evaluation (Table 2), Gerais (FAPEMIG).
BDBM6732 presented significant risks of mutagenesis,
making it unsuitable for therapeutic use. To overcome this Funding
problem, we used the BDBM6732’s backbone structure to We are thankful to the Foundation for Research Support of
design a series of analogs intended to retain or improve the State of Minas Gerais (FAPEMIG), Brazil, for funding
affinity for the N protein’s C-terminal region and improve the scientific initiation scholarship and, consequently, for
safety profiles. Afterward, we created several similar making this project viable.
compounds that showed increased binding affinity to the
target receptor (Table 2) and displayed favorable ADME- Conflict of interest
Tox properties, particularly the lack of mutagenic potential The authors declare that they have no conflicts of interest.
as verified by AMES test results (Table 4). These results
highlight the potential of drug design in improving primary Author contributions
compounds to achieve effectiveness and safety, setting the Conceptualization: Amanda Bubula de Souza, Nelson José
stage for developing new treatments. Based on the results, Freitas da Silveira
we decided to select BDBM6732-bio2 and BDBM6732- Investigation: Amanda Bubula de Souza, Leonardo Pereira
bio1 as the optimal prototype substances for synthesizing de Araújo, Amanda Almeida Morais, Leandro Marcos
and subsequent experimental cell activation assays.
Santos, Yana Cristina Albanez Santos, Cássia Milene
5. Conclusion Ribeiro Lopes, Nelson José Freitas da Silveira
Methodology: Amanda Bubula de Souza, Leonardo Pereira de
Although COVID-19, caused by the SARS-CoV-2 virus, Araújo, Amanda Almeida Morais, Leandro Marcos Santos
has been somewhat controlled, it still represents a global Writing –original draft: Amanda Bubula de Souza, Nelson
problem due to severe symptoms affecting the respiratory José Freitas da Silveira, Paulo Vinicius Sanches Daltro
and other human biological systems. This study employed de Carvalho, Syed Shah Hassan
drug repositioning and bioisosterism strategies to identify Writing– review & editing: Leonardo Pereira de Araújo,
novel compounds with potential activity against the N Amanda Almeida Morais, Leandro Marcos Santos
protein of the SARS-CoV-2 virus. The study identified
two proposed analogs that exhibited a higher affinity Ethics approval and consent to participate
for the molecular target than the backbone structure of Not applicable.
BDBM6732. Furthermore, these analogs demonstrated
superior affinity to four compounds referenced in the Consent for publication
scientific literature, two of which had their activity validated
in vivo. In addition, an evaluation of the ADME-Tox Not applicable.
properties of the two selected analogs revealed favorable Availability of data
pharmacokinetic and pharmacodynamic profiles, thereby
strengthening their potential as promising candidates for Data are available from the corresponding author upon
the treatment of COVID-19. These findings emphasize the reasonable request.
effectiveness of using drug repositioning and bioisosterism
techniques to discover new therapeutic agents for treating References
COVID-19. In further studies, it is decided to prioritize 1. Markov PV, Ghafari M, Beer M, et al. The evolution of
synthesizing two promising analogs (BDBM6732-bio2 and SARS-CoV-2. Nat Rev Microbiol. 2023;21(6):361-379.

Volume 1 Issue 1 (2024) 123 doi: 10.36922/imo.3731