In silico study of the interaction of insect, scorpion and frog venom peptides with the spike protein receptor binding domain of coronavirus: investigation of natural inhibitors of SARS-CoV-2
In silico study of the interaction of insect, scorpion and frog venom peptides with the spike protein receptor binding domain of coronavirus: investigation of natural inhibitors of SARS-CoV-2
Mohadeseh Amini,1Fatemeh Karimi,2Mohammadreza Ganjalikhany,3,*
1. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran 2. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran 3. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
Introduction: The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with the angiotensin-converting enzyme 2 (ACE2) receptor in human cells and causes covid-19 infection. This protein is located on the virus membrane and is a triangular glycoprotein with two S1 and S2 domains, both of which are very important for SARS-CoV-2 infection. Interactions between S1 with the peptidase domain of ACE2 lead to the binding of the virus to the host, and then the S2 domain leads to membrane fusion and entry of the viral ribonucleoprotein complex and its entry into the host cell. RBD (receptor binding domain) of the S1 domain of spike protein represents a potential target for the development of anti-SARS-CoV-2 drugs which might have the potential to inhibit the entry of SARS-CoV-2 into the host cells. Then, we considered the interaction of the RBD domain with ACE2. Peptides are potential molecules to be tested against spike protein. Then some peptides targeting the spike protein to prevent infection by COVID-19 establishment were investigated. Considering the importance of spike protein interaction with ACE2 receptor, some antiviral peptides of the scorpion, insect, and frog venom were selected and their docking and molecular binding analysis with the RBD domain of coronavirus spike protein have been done.
Methods: In order to select a proper peptide for binding to SARS-CoV-2 spike protein of coronavirus, 22 small peptides from venom scorpion, frog and, insect were obtained via literature survey.
Molecular modeling: There are various servers and software for modeling peptides. PEPfold3 server was used in this research because all peptides had less than 50 amino acids.
Docking: In this research, the HADDOCK server was used for molecular docking for protein-protein interaction. The crystal structure of the RBD domain in complex with the ACE2 receptor is available in the PDB bank and was used in this study (PDB code: 6m17, chain E). Then, only the RBD domain of the spike protein was used. All 22 structures obtained from various antiviral toxins were considered for docking, and each peptide was individually docked to the RBD domain of spike protein through the HADDOCK server. The binding residues that interact with ACE2 receptor were considered active residues in docking and included Lys 417, Tyr 453, Gln 474, Phe 486, Gln 498, Thr 500, and Asn 501. Also, all residues from peptides are considered active residues. The interaction between peptides and the RBD domain in each complex was obtained using Ligplot+ software and the prodigy server.
Results: All the 22 peptides that were modeled by the Pepfold3 server were analyzed in the Haddock server in terms of the degree of binding to the RBD domain. The results showed that 5 Venom antimicrobial peptides-9, Dermaseptin-s4, Magainins1, caerin1-9, and Magainins2 have a lower Haddock score than the control.
Hence, they have a stronger binding affinity to the RBD of the domain. Two peptides Venom antimicrobial peptide-9 and Magainins1 with Haddock scores of -121.6 and -119.6 are the best in terms of binding score. Also, by comparing the hydrogen bonds between the receptor and the ligand in the control state and the two best states, it was shown that in the two top states, the interaction with active residues was more desirable. Therefore, these two peptides are better than the control, both in terms of the docking score and in terms of making hydrogen bonds with the desired points, and it is suggested that they can perform better in binding to the RBD of the domain with better quality than the binding of this domain to ACE2 and therefore, prevent the host cells from causing covid-19.
Conclusion: According to the obtained results, Venom Antimicrobial Peptide 9 (FFGHLFKLATKIIPSLFQ) and maginin (GIGKFLHSAGKFGKAFVGEIMKS) interacted better with the RBD domain of spike protein than other peptides. Among these two peptides, Venom Antimicrobial Peptide 9 with RBD domain interacts more effectively than Magainins. And it can inhibit the interaction of the spike protein with the ACE2 receptor, so the peptide "FFGHLFKLATKIIPSLFQ" can be considered as a potential drug for the disease of COVID-19.