Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Jul 27, 2023; 14(4): 72-83
Published online Jul 27, 2023. doi: 10.4331/wjbc.v14.i4.72
In silico evidence of Remdesivir action in blood coagulation cascade modulation in COVID-19 treatment
Luis Gustavo Pagliarin, Lucca Miketen de Oliveira, Valentina Nunes Fontoura dos Anjos, Cristiano de Bem Torquato de Souza, Gabrielle Caroline Peiter, Cinthia Façanha Wendel, Anderson Dillmann Groto, Fabrício Freire de Melo, Kádima Nayara Teixeira
Luis Gustavo Pagliarin, Lucca Miketen de Oliveira, Valentina Nunes Fontoura dos Anjos, Cristiano de Bem Torquato de Souza, Cinthia Façanha Wendel, Anderson Dillmann Groto, Kádima Nayara Teixeira, Campus Toledo, Universidade Federal do Paraná, Toledo 85.919-899, Paraná, Brazil
Gabrielle Caroline Peiter, Kádima Nayara Teixeira, Programa Multicêntrico de Pós-graduação em Bioquímica e Biologia Molecular - Setor Palotina, Universidade Federal do Paraná, Palotina 85.950-000, Paraná, Brazil
Fabrício Freire de Melo, Instituto Multidisciplinar em Saúde - Campus Anísio Teixeira, Universidade Federal da Bahia, Vitória da Conquista 45.029-094, Bahia, Brazil
Author contributions: Pagliarin LG, Oliveira LM, Anjos VNF, and Souza CBT performed the experiments, analyzed the results, and wrote the manuscript; Peiter GC, Wendel CF, and Groto AD performed the experiments; Melo FF performed the critical analysis of the results; Teixeira KN interpreted the data, performed the critical analysis of the results, corrected the manuscript, and coordinated the study; all authors approved the final version of the manuscript.
Institutional review board statement: This study used data from three-dimensional structures deposited in public online databases.
Conflict-of-interest statement: The authors state that there is no conflict of interest of any kind with regard to this study.
Data sharing statement: This study was developed in silico and no patient data or data from medical records were used in this study.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kádima Nayara Teixeira, PhD, Professor, Campus Toledo, Universidade Federal do Paraná, Max Planck 3796, Toledo 85.919-899, Paraná, Brazil. kadimateixeira@ufpr.br
Received: December 30, 2022
Peer-review started: December 30, 2022
First decision: April 13, 2023
Revised: April 30, 2023
Accepted: July 3, 2023
Article in press: July 3, 2023
Published online: July 27, 2023
Processing time: 206 Days and 8.3 Hours
Abstract
BACKGROUND

Coronavirus disease 2019 (COVID-19) has demonstrated several clinical manifestations which include not only respiratory system issues but also liver, kidney, and other organ injuries. One of these abnormalities is coagulopathies, including thrombosis and disseminated intravascular coagulation. Because of this, the administration of low molecular weight heparin is required for patients that need to be hospitalized. In addition, Remdesivir is an antiviral that was used against Middle East Acute Respiratory Syndrome, Ebola, Acute Respiratory Syndrome, and other diseases, showing satisfactory results on recovery. Besides, there is evidence suggesting that this medication can provide a better prognosis for patients with COVID-19.

AIM

To investigate in silico the interaction between Remdesivir and clotting factors, pursuing a possibility of using it as medicine.

METHODS

In this in silico study, the 3D structures of angiotensin-converting enzyme 2 (ACE2), Factor I (fibrinogen), Factor II (prothrombin), Factor III (thromboplastin), Factor V (proaccelerin), Factor VII (proconvertin), Factor VIII (antihemophilic factor A), Factor IX (antihemophilic factor B), Factor X (Stuart-Prower factor), and Factor XI (precursor of thromboplastin (these structures are technically called receptors) were selected from the Protein Data Bank. The structures of the antivirals Remdesivir and Osetalmivir (these structures are called ligands) were selected from the PubChem database, while the structure of Atazanavir was selected from the ZINC database. The software AutoDock Tools (ADT) was used to prepare the receptors for molecular docking. Ions, peptides, water molecules, and other ones were removed from each ligand, and then, hydrogen atoms were added to the structures. The grid box was delimited and calculated using the same software ADT. A physiological environment with pH 7.4 is needed to make the ligands interact with the receptors, and still the software Marvin sketch® (ChemAxon®) was used to forecast the protonation state. To perform molecular docking, ADT and Vina software was connected. Using PyMol® software and Discovery studio® software from BIOVIA, it was possible to analyze the amino acid residues from receptors that were involved in the interactions with the ligands. Ligand tortions, atoms that participated in the interactions, and the type, strength, and duration of the interactions were also analyzed using those software.

RESULTS

Molecular docking analysis showed that Remdesivir and ACE2 had an affinity energy of -8.8 kcal/moL, forming a complex with eight hydrogen bonds involving seven atoms of Remdesivir and five amino acid residues of ACE2. Remdesivir and prothrombin had an interaction with six hydrogen bonds involving atoms of the drug and five amino acid residues of the clotting factor. Similar to that, Remdesivir and thromboplastin presented interactions via seven hydrogen bonds involving five atoms of the drug and four residues of the clotting factor. While Remdesivir and Factor V established a complex with seven hydrogen bonds between six antiviral atoms and six amino acid residues from the factor, and Factor VII connected with the drug by four hydrogen bonds, which involved three atoms of the drug and three residues of amino acids of the factor. The complex between Remdesivir and Factor IX formed an interaction via 11 hydrophilic bonds with seven atoms of the drug and seven residues of the clotting factor, plus one electrostatic bond and three hydrophobic interactions. Factor X and Remdesivir had an affinity energy of -9.6 kcal/moL, and the complex presented 10 hydrogen bonds and 14 different hydrophobic interactions which involved nine atoms of the drug and 16 amino acid residues of the clotting factor. The interaction between Remdesivir and Factor XI formed five hydrogen bonds involving five amino acid residues of the clotting factor and five of the antiviral atoms.

CONCLUSION

Because of the in silico significant affinity, Remdesivir possibly could act in the severe acute respiratory syndrome coronavirus 2 infection blockade by interacting with ACE2 and concomitantly act in the modulation of the coagulation cascade preventing the hypercoagulable state.

Keywords: Clotting factors; Coagulating blood cascade; COVID-19 treatment; Remdesivir; SARS-CoV-2

Core Tip: In the initial period of the emergence of coronavirus disease 2019, bioinformatics tools filled the need for rapid knowledge about the severe acute respiratory syndrome coronavirus 2 and research in search of drug treatment, since experimental research takes time that was not available. Bioinformatics continues to be used for the same purpose in this study, remembering that this methodology does not rule out either in vivo or in vitro testing.