IN SILICO INSPECTION OF BIOMOLECULAR INTERACTIONS BETWEEN FLUVOXAMINE ANALOGUES AND SARS-COV-2 PROTEIN RECEPTORS

IN SILICO INSPECTION OF BIOMOLECULAR INTERACTIONS BETWEEN FLUVOXAMINE ANALOGUES AND SARS-COV-2 PROTEIN RECEPTORS

• Author
• Milena Ornilo da Silva
• Co-authors
• Deyvid Felipe Araújo , Jenipher Stephanie Pereira das Neves , Edson Luiz Folador
• Abstract

• IN SILICO INSPECTION OF BIOMOLECULAR INTERACTIONS BETWEEN FLUVOXAMINE ANALOGUES AND SARS-COV-2 PROTEIN RECEPTORS

   

  Milena Ornilo da Silva; Deyvid Felipe Araújo; Jenipher Stephanie Pereira das Neves; Edson Luiz Folador.

   

  SARS-CoV-2, known as coronavirus, was initially identified in December 2019 in the city of Wuhan, in Hubei province, China. This virus belongs to the Coronaviridae family, which also includes pathogens such as Severe Acute Respiratory Syndrome (SARS) virus and Middle East Respiratory Syndrome (MERS) virus.The disease caused by SARS-CoV-2 was called COVID-19, and it quickly spread to other areas of China and later to several countries around the world, culminating in a global pandemic.Its spread was facilitated by easy contagion between people, occurring even before the appearance of visible symptoms.The scientific community responded exceptionally, dedicating itself to understanding the virus, developing tests, therapies and, eventually, vaccines.Governments around the world have implemented strict measures, including social distancing, widespread use of masks and travel restrictions, to contain the spread of the virus and protect public health.Even with the introduction of vaccines, the constant emergence of new variants of the virus represents a threat to the effectiveness of immunization. These variants may prove more contagious and less responsive to vaccines, potentially resulting in immune system evasion and decreased effectiveness of available vaccines.Therefore, it is still necessary to search for effective antiviral medications and treatments, aiming to reduce the severity of symptoms and control the disease, playing a fundamental role in protecting the population.The identification of new medicines involves the use of computational methods that analyze several drug options, identifying promising molecules for subsequent biological experiments.These techniques allow for effective and cost-effective screening, considerably accelerating the drug development process. Fluvoxamine is a selective serotonin reuptake inhibitor and sigma 1 receptor agonist, used in the treatment of depression and obsessive compulsive disorder and anxiety disorders such as panic disorder and post-traumatic stress disorder. During the COVID-19 pandemic, some studies and research suggested that fluvoxamine could have beneficial effects in treating the disease. However, it is important to note that the effectiveness of fluvoxamine in treating COVID-19 has not been conclusively established and continues to be the subject of studies and debates in the scientific community. Promoting the reuse of existing medicines is driven by the advantage of taking advantage of prior knowledge about safety, dosage and complications. Furthermore, this approach is more affordable, making it viable for large-scale implementation. Therefore, computational techniques show promise in identifying fluvoxamine analogues with potential antiviral action against SARS-CoV-2, contributing to the development of new treatments for COVID-19.

   

  AIMS

  This work aims to identify possible molecules analogous to FLUVOXAMINE, which present antiviral activity against SARS-CoV-2, based on protein-ligand interaction, through the search for similar pharmacophoric groups and evaluation of pharmacokinetic and toxicity properties.

   

  METHODS
  Collection and adaptation of the files using OpenBabel - converter (.pdbqt to .mol2), then the files were loaded into the Pharmit Search Engine and the search was used in some databases (Chembl32, ChemDiv, ChemSpace, MCULE, MCULE- Ultimate PubChem and ZINC). Furthermore, the filters were applied and the results were obtained; (Hit screening: 0 - 500 mass 0 - 6 logP 0 - 6 Rotatable lig. 0 - 12 acceptors 0 - 6 donors) and, finally, the best results were evaluated in ADMETLab 2.0.

   

  RESULTS AND DISCUSSION
  Molecules analogous to fluvoxamine with the best affinity scores showed high toxicity, therefore, a search was carried out for similar pharmacophoric groups in order to find analogues of these candidates with promising affinity scores, in addition to good pharmacokinetic properties and lower toxicity. The result of this search produced 2,521 compounds with affinity values ??more negative than -8.50 kcal/mol, from different sources, including 1,342 from ZINC, 229 from PubChem, 199 from ChemDIV, 79 from ChemSpace, 366 from CHEMBL32, 285 from MCULE and 21 from MCULE-Ultimate. In total, 127 molecules had their ADMET properties analyzed and presented satisfactory results in absorption, metabolism, distribution, excretion and lower toxicity compared to nitazoxanide, being subjected to a more detailed analysis to select the best ones. Finally, 8 molecules achieved the best performances, and 3 of them did not show toxicity in in silico tests. Only analogues M1, M3 and M5 showed the potential to cause drug-induced liver injury. However, all of its other parameters were approved, with better results than the model drug. After the analyzes carried out, it was found that analogues A5 and A9 have excellent characteristics in terms of toxicity points, also approved under the Lipinski and Pfizer rules. Furthermore, fluvoxamine has a value considered unfavorable with regard to the respiratory toxicity parameter. This fact must be carefully considered as a disadvantage for medicines aimed at treating COVID-19. Therefore, all molecules that showed this type of toxicity were promptly excluded. In this way, all the molecules that presented the best results obtained fewer toxicity points when compared to the model drug.

   

  CONCLUSION
  With reference to previous research, Fluvoxamine was identified as a possible candidate with potential pharmacological activity against COVID-19. Studies have been conducted, providing evidence of its effectiveness against the virus. These discoveries motivated the present study, which involved the creation of a library of analogous compounds, showing chemical similarity to Fluvoxamine. Subsequently, the model drug analogues underwent virtual screening, energy minimization and analysis of pharmacokinetic properties. In the ADMET property analyses, 8 molecules (D1, D3, D4, D5, M1, M2, M4, M5) were identified with promising results. Among them, 3 molecules proved to be non-toxic in all parameters related to toxicity, with only one approved in all toxicity parameters and in the Lipinski and Pfizer rules. The molecules received an alphanumeric nomenclature to preserve their identities due to the possibility of carrying out future work. All met the SAscore parameter, which evaluates the ease of synthesis. The effectiveness of the approach of searching for pharmacophoric groups in obtaining compounds that, in silico, present greater affinity and lower toxicity than Fluvoxamine is evident. The molecules presented favorable pharmacological profiles, indicating that the search for pharmacophores proved to be an effective strategy in obtaining compounds with higher affinity and more favorable in silico toxicity compared to Fluvoxamine, which justifies its consideration for future in vitro tests.
   

  ACKNOWLEDGMENT:
  Lambda - Laboratório Multiusuário de Bioinformática e Análise de Dados
  UFPB - Universidade Federal da Paraíba 

   

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• Keywords
• Molecular docking; Virtual screening; Pharmacophore analysis; Molecular dynamics simulations; Bioinformatics analysis; Drug repurposing; Binding affinity; Protein structure prediction.
• Modality
• Pôster
• Subject Area
• Quimioinformatics, Bioinformatics and TheoreticalChemistry