Simulation of the inhibitory effect of common antiviral drugs on Spike glycoprotein for the treatment of infections caused by Covid19

Simulation of the inhibitory effect of common antiviral drugs on Spike glycoprotein for the treatment of infections caused by Covid19
Zeinab Norouzi Tabrizi Nejad,^1,* Razieh Norouzi Tabrizi Nejad,²
1. Shahid Chamran University of Ahvaz
2. Ahvaz Jundishapur University of Ahvaz
Introduction: Coronavirus is a type of enveloped viruses and it has a size of about 120 to 160 nm and contains a single strand RNA genome fragment and it is known as one of the largest RNA viruses. Coronavirus consists of four genera: alpha, beta, gamma and delta, and tow genera alpha and beta cause disease in humans. At the beginning of the new year (2020), the Coronavirus caused a global epidemic that has so far spread to more than 200 countries and more than 24 million people worldwide have been infected with Covid 19 disease; and More than 800,000 people around the world have died from modern coronavirus infections; And because of extensive genomic changes,in this virus, So far, no effective vaccine or drug has been introduced for it. Covid 19 belongs to the class of beta-coronaviruses. On the outer surface of the virus coat, there are stick-shaped protrusions about 20 nanometers long that create a sun-like appearance and act as the virus-binding protein to its receptor in lung tissue, and called the spike glycoprotein. To be Studies have shown that the ACE2 protein is a coronavirus receptor, and for coronavirus pathogenic function, it must first bind to the receptor in lung, esophageal, epithelial, and colon cells. Connect. After binding of Spike glycoprotein to its ACE2 receptor, the virus protein is broken down by proteolysis by catepsin or furin proteinase, and the virus coat fuses with the cell membrane. Common symptoms of Covid 19 infections include fever, fatigue, muscle aches, cough, and shortness of breath, and myocarditis, diarrhea, and vomiting are rare. The aim of this study was to introduce the best inhibitor through molecular interaction between spike protein and existing antiviral drugs.
Methods: The sequence of Spike SARS2( surface glycoprotein [Severe acute respiratory syndrome coronavirus 2]) with Accession: QJX59884.1 was retrieved from NCBI website (www.ncbi.nlm.nih.gov/protein) in FASTA format. The modeling and energy minimization experiment were performed on SWISS-MODEL server (https://swismodelexpacy.org) and From Five models extracted here the best one was selected based on RAMPAGE analysis(https://servicesn.mbi.ucla.edu/PROCHECK/) and used for further experiments. This structure then refined for blind docking experiments in HEX (version 8.0.0). The docking experiments were done using 60 different available antiviral drugs to study their interactions and to survey their bind sites. Coordinate structures of 60 antiviral drugs were designed in .PDB format with ChemDraw Professional 15.0 software and optimized in ArgusLab. software. Docking results were analyzed in ArgusLab, PyMOL, LigPlus and WebLab Viewer softwares and finally Evaluation of the toxicity effect of selected drugs were performed on adverpred server (http://www.way2drug.com/adverpred/).
Results: Spike protein simulation showed that this protein has three chains A, B and C, and each chain of this protein contains 1147 amino acids, and the first amino acid is Ala27 and the last amino acid is Ser1147, and 26 amino acids are in the N-terminal caudal region. The results of molecular docking of drugs and Spike protein showed that Ampligen, Atazanavir, Cobicistate, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Remdesivir, Ritonavir, Telaprevir and Tripranavir have higher and more favorable negative binding energy and better connected to the protein binding site. The results of this study showed that Spike glycoprotein has a binding site in all three subunits, and the amino acids Arg1968, Cys1972, Ala1973, Lys1975 and Phe1976 are common binding sites of selected drugs and Remdesivir binds to subunits A and C.
Conclusion: Spike glycoprotein after binding to its receptor, it is broken down by the enzyme proteinase into two subunits S1 containing the Protein binding domain and subunit S2. The results of this study showed that Atazanavir, Cobicistate, Indinavir and Lopinavir by binding to the Spike protein and restrain it, inhibits the enzymatic break down of this glycoprotein and prevent the S1 subunit from binding to its receptor in the cell.
Keywords: Spike, Covid19, Lopinavir, Binding site, ACE2