IN SILICO EVALUATION OF THE BINDING POTENTIAL OF FLUVOXAMINE ANALOGS AGAINST SARS-COV-2 PROTEINS

Shayenne Eduarda Ramos Vanderley; Gabriel Teodozio dos Santos; João Pedro Gonçalves Ribeiro; Antonio Mauro Rezende; Edson Luiz Folador

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Submission

Paper Title

IN SILICO EVALUATION OF THE BINDING POTENTIAL OF FLUVOXAMINE ANALOGS AGAINST SARS-COV-2 PROTEINS

Authors

Shayenne Eduarda Ramos Vanderley
Gabriel Teodozio dos Santos
João Pedro Gonçalves Ribeiro
Antonio Mauro Rezende
Edson Luiz Folador

Modality

Xpress presentation

Subject area

Structural Bioinformatics

Publishing Date

26/04/2022

Country of Publishing

Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeetingxp2021/411346-in-silico-evaluation-of-the-binding-potential-of-fluvoxamine-analogs-against-sars-cov-2-proteins

ISBN

978-65-5941-645-5

Keywords

Drug discovery, Virtual screening, SBVS, LBVS, COVID-19

Summary

COVID-19 is a highly transmissible viral infectious disease, responsible for thousands of deaths worldwide. Mutations in the SARS-CoV-2 genome cause resistance to immune responses induced by vaccines, motivating the search for more effective therapies. Thus, we aim in this study to identify analogs of Fluvoxamine, a drug that demonstrated in vitro efficacy against COVID-19, and to test a potential antiviral action against SARS-CoV-2 proteins. In order to mimic the ensemble docking methodology, 967 SARS-CoV-2 target proteins were selected from the PDB database, discarding 480 structures having RMSD <0.5Å when compared to each other. Using fpocket, we identified protein pockets with a druggability score >= 0.5. Fluvoxamine analogs were downloaded from the ZINC database (30% similarity) and the PubChem database (substructures), totaling 14 and 169 analogs respectively. Using the QuickVina 2 program, we tested the affinity of each analog against the SARS-CoV-2 target protein pockets. Receptor-ligand complexes with affinity greater than -6 Kcal/mol were discarded, totaling 108,866 complexes, 100,641 having higher affinity than the drug fluvoxamine (-8.90 Kcal/mol). The 6 best complexes showed affinity greater than -12.20 Kcal/mol: A1, A3, A4 and A5 with the Spike protein; A2 and A3 with NSP3. The pharmacokinetic parameters of the 5 best analogs were predicted in pkCSM: all violate RO5 rules; in the parameters of intestinal absorption they obtained: A1 35.27%; A2: 100%; A3: 68.83%; A4: 100% and A5: 0%. A1, A3 and A4 demonstrated to have a hepatotoxic feature, different from fluvoxamine. The affinity of the top 3 complexes was visually analyzed using the PyMOL software and Discovery Studio Visualizer to assess two-dimensional protein-ligand interactions. Both analogs A1 and A3 anchored to the internal pockets of Spike, A1 to the upper outer portion of the protein and A3 to a cavity in the transmembrane portion. A3 also docked in an NSP3 external pocket. Fifteen interactions between Spike and analogs A1 and A3 were observed: A1 binds to protein S in an extremely conserved region and is related to an independent mechanism of immune dysregulation and inflammation; oppositely, A3 binds to Spike near the TMPRSS2 cleavage zone of the S1 and S2 subunits of the protein, responsible for viral fusion to the host membrane. However, no interaction with amino acids common to the protease and the compound was found. Furthermore, 9 interactions were identified between NSP3 and A3: 8 are interactions located at the Mac1 active site, important for viral replication and inhibiting the host cells antiviral state, 2 of those interactions are formed by hydrogen bonds. Based on the data, compounds A1 and A3 have the potential to act as pharmacological inhibitors of SARS-CoV-2. Additionally, A1 and A3 are promising candidates for the rational design process and optimization of their structures in order to provide greater affinity and specificity to the target protein. Further in vitro analyzes are needed to confirm the results obtained.

Title of the Event: X-Meeting XPerience 2021
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

VANDERLEY, Shayenne Eduarda Ramos et al.. IN SILICO EVALUATION OF THE BINDING POTENTIAL OF FLUVOXAMINE ANALOGS AGAINST SARS-COV-2 PROTEINS.. In: X-Meeting presentations. Anais...São Paulo(SP) AB3C, 2021. Available in: https//www.even3.com.br/anais/xmeetingxp2021/411346-IN-SILICO-EVALUATION-OF-THE-BINDING-POTENTIAL-OF-FLUVOXAMINE-ANALOGS-AGAINST-SARS-COV-2-PROTEINS. Access in: 09/10/2024