Inspection of biomolecular interactions between remdesivir analogues against SARS-CoV-2 structural and non-structural protein receptors

Inspection of biomolecular interactions between remdesivir analogues against SARS-CoV-2 structural and non-structural protein receptors

• Author
• Vitoria Fernandes Ferro
• Co-authors
• Beatriz Frederico Oliveira Silveira , Edson Luiz Folador
• Abstract

•  

  Inspection of biomolecular interactions between remdesivir analogues against SARS-CoV-2 structural and non-structural protein receptors

  Vitoria Fernandes Ferro; Beatriz Frederico Oliveira Silveira; Edson Luiz Folador.

   

  INTRODUCTION

  The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in 2019 generated devastating consequences across the world. In 2020, the World Health Organization (WHO) declared a global pandemic in light of the chaotic scenario due to the virus's easy transmissibility, causing social and economic damage. SARS-COV-2 rapidly evolves into highly contagious variants around the world, which has the potential to impact the effectiveness of vaccines and requires the implementation of more than one dose. Although vaccines have been used to prevent COVID-19 infection, attempts have been made to reduce the worsening of symptoms by using antiviral medications. Among them, remdesivir or Veklury® was approved by the National Health Surveillance Agency (ANVISA) in 2022 for the treatment of COVID-19, in order to prevent the virus from replicating in the body, reducing the infection process. Remdesivir is an adenosine nucleotide prodrug with antiviral action against RNA viruses, having a broad spectrum of activity, with the inhibition of the virus's RNA-dependent RNA polymerase enzyme (RpdR). The drug was initially designed to treat hepatitis C, but was later used to treat Ebola virus disease and Marburg virus infections. However, the clinical benefit is not clear, as it has been reported that the use of remdesivir for the treatment of COVID-19 may cause adverse events such as respiratory failure, significant increase in liver enzymes, low red blood cell count, reduction in the number of platelets, increased blood sugar levels, kidney failure and hypotension. Given this scenario, computational methods become allies in the prior search for new medicines, with a quick and low-cost approach in the search for analogues of already known drugs, such as remdesivir, overcoming their adversities and contributing to the treatment of COVID-19 more safely and effectively.

   

  AIMS

  The present work aims to identify and analyze different remdesivir analogues with antiviral action against SARS-CoV-2, evaluating the toxicological and pharmacokinetic characteristics, selecting potential molecules with better parameters for future in-vitro clinical phase tests.

   

  METHODS

  The work was divided into several stages, starting with the Ligand-Based Virtual Screening (LBVS) phase, where molecules similar to remdesivir were extracted from the ZINC and PubChem databases, with the search being based on substructures in Pubchem and search for molecules with at least 50% similarity to the reference drug in ZINC. In the Structure-based Virtual Screening (SBVS) stage, through the PDB database it was possible to obtain different conformations of proteins related to SARS-CoV-2. Pockets were predicted using the fpocket 4.0 software, regions that will interact with ligand molecules, and those with a druggability score greater than or equal to 0.5 were selected. Docking was carried out using the QuickVina 2.1 software considering different orientations and conformations of the molecules, obtaining protein-ligand complexes and selecting those with the lowest kcal/mol scores. The SARS-CoV-2 target proteins selected were 7A93, 7CAB, 7KMS, 7KNI and 7KR1. In Pharmit, the pharmacophores of analogues were searched, using specific filters to optimize the number of favorable hits. The selection criteria used to filter the analogues was based on the score, discarding those with values much more positive than remdesivir (-10.5 kcal/mol). Then, the analogues with the best score were subjected to cytotoxicity and medicinal chemistry analyzes in ADMETlab 2.0.

   

  RESULTS AND DISCUSSION

  When searching for remdesivir analogues with a more negative score than the drug, 125 results were analyzed and among them 88 were from Pubchem and 37 from Zinc. Priority was given to parameters aimed at toxicity analysis, obtaining three promising analogues after evaluating toxicity, medicinal chemistry, absorption, distribution and excretion. The analogues were identified as A2.1, A5.1 and A5.3, respectively with scores -12.15, -12.4 and -10.49. Toxicity levels were considerably lower than remdesivir in in silico testing, offering potential for these molecules. Only one of the selected molecules, A5.3, had a slightly more positive score (-10.49 kcal/mol) than remdesivir (-10.5 kcal/mol). However, it has a low probability of causing respiratory toxicity, presenting satisfactory results for the Ames test for mutagenicity, together with the FDAMDD, maximum recommended daily dose. This case brings to light discussions that can be traced between the value of the score and the pharmacokinetic and toxicological properties of the molecule. In other words, a satisfactory score does not always mean a better result in ADMET standards, making a balance between these variables a fundamental characteristic. Remdesivir, despite being used to treat COVID-19, has a high probability (0.963) of causing respiratory toxicity, which is not a desirable characteristic as patients infected with the disease have their respiratory tract affected and may experience Severe Acute Respiratory Syndrome (SARS), responsible for causing deaths and hospital admissions. Therefore, analogues that were highly likely to cause respiratory toxicity were discarded as they were not ideal for treating the disease. Furthermore, remdesivir also has a high probability (0.963) of causing drug-induced liver damage (DILI). The Ames test for mutagenicity also does not show satisfactory results, along with the FDAMDD, maximum recommended daily dose. Taking these main points into consideration, the selection of analogues with better characteristics than the drug itself was prioritized, becoming potential molecules for in vitro analysis.

   

  CONCLUSION

  The importance of virtual drug screening can be seen in this study, especially in pandemic situations, as it allows the optimization of drug development through procedures and tools that monitor molecular anchoring and their respective pharmacokinetic and toxicological profiles. Remdesivir is a medicine used to treat COVID-19, but its clinical advantages are not clear, with several studies pointing to the adverse effects caused by the medicine. Therefore, analogues of remdesivir were obtained and their advantages were highlighted, mainly related to the reduction of respiratory toxicity, which is quite evident in the medicine, which may be contradictory to its use in cases of SARS-CoV-2. For this study to be carried out, a library of remdesivir analogues was obtained and virtual screening, energy minimization and analysis of the pharmacokinetic properties of all analogues with a score higher than the drug itself were carried out. By analyzing the characteristics of toxicity, medicinal chemistry, absorption, distribution and excretion, three promising analogues were selected, A2.1, A5.1 and A5.3, which will have their names preserved due to the possibility of future studies. In general, the three selected analogues had better and more satisfactory results than the medicine itself, with favorable pharmacological profiles that interact with the active sites of SPIKE and NSP3. This study is based on an extensive analysis using different databases, filtered in order to obtain only the most promising analogues from a huge set of possibilities. Given these results, this research paves the way for the chemical synthesis of medicines that aim to mitigate the impact of SARS-CoV-2 on public health in a safe and effective way using bioinformatics as a starting point.

   

  ACKNOWLEDGMENT

  Author and co-author would like to acknowledge CNPQ, UFPB, CBiotec e LAMBDA for his substantial support and offering us the opportunity to do this work.

   

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• Keywords
• COVID-19, Remdesivir, Analogues
• Modality
• Pôster
• Subject Area
• Quimioinformatics, Bioinformatics and TheoreticalChemistry