Identification of potential Indonesian marine invertebrate bioactive compounds as TMPRSS2 and SARS-CoV-2 Omicron spike protein inhibitors through computational screening

Abstract

The coronavirus pandemic led to the announcement of a worldwide health emergency. The SARS-CoV-2 Omicron variant, which swiftly spread worldwide, has fueled existing challenges. Appropriate medication is necessary to avoid severe SARS-CoV-2 disease. The human TMPRSS2 and SARS-CoV-2 Omicron spike protein, which are required for viral entry into the host phase, were identified as the target proteins through computational screening. Structure-based virtual screening; molecular docking; absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis; and molecular dynamics simulation were the methods applied for TMPRSS2 and spike protein inhibitors. Bioactive marine invertebrates from Indonesia were employed as test ligands. Camostat and nafamostat (co-crystal) were utilized as reference ligands against TMPRSS2, whereas mefloquine was used as a reference ligand against spike protein. Following a molecular docking and dynamics simulation, we found that acanthomanzamine C has remarkable effectiveness against TMPRSS2 and spike protein. Compared to camostat (-8.25 kcal/mol), nafamostat (-6.52 kcal/mol), and mefloquine (-6.34 kcal/mol), acanthomanzamine C binds to TMPRSS2 and spike protein with binding energies of -9.75 kcal/mol and -9.19 kcal/mol, respectively. Furthermore, slight variances in the MD simulation demonstrated consistent binding to TMPRSS2 and spike protein after the initial 50 ns. These results are highly valuable in the search for a treatment for SARS-CoV-2 infection.

Keywords: ADMET; Marine invertebrates; Molecular docking; Molecular dynamics; SARS-CoV-2; TMPRSS2.

Fig. 1

Superposition of macromolecules before and after modeling: A) TMPRSS2 loop before (orange dotted line) and after modeling (blue line) and B) SARS-CoV-2 Omicron variant spike protein chain C loop before (red dotted line) and after modeling (blue line).

Fig. 2

Interaction of amino acid residues TMPRSS2 with reference ligands: A) Camostat’s interaction with TMPRSS2 amino acid residues and B) nafamostat’s interaction with TMPRSS2 amino acid residues.

Fig. 3

Result of TMPRSS2 protein docking (PDB ID: 7MEQ) with Omicron variant SARS-CoV-2 spike protein (PDB ID: 7QO7) at cleavage site 1 active residue 686 and 685 (red residues). The SARS-CoV-2 Omicron variant spike protein is represented by magenta, while TMPRSS2 is represented by blue.

Fig. 4

Alignment of nafamostat (A) and mefloquine (B) for validation of the TMPRSS2 protein and the SARS-CoV-2 Omicron spike protein, respectively. The light blue color indicates the position of the ligand before redocking, while the light green color shows its position after redocking.

Fig. 5

Interactions of the reference ligands (camostat and nafamostat) and the test ligands (acanthomanzamine C and cortistatin G) with TMPRSS2 amino acid residues.

Fig. 6

Interactions of the reference ligand (mefloquine) and the test ligands (acanthomanzamine C and cortistatin J) with SARS-CoV-2 Omicron spike protein amino acid residues.

Fig. 7

RMSD results for 100 ns: A) ligands in a complex with the TMPRSS2 and B) ligands in a complex with the SARS-CoV-2 Omicron spike protein.

Fig. 8

RMSF results for 100 ns: A) amino acid residues of the TMPRSS2 and B) amino acid residues of the SARS-CoV-2 Omicron spike protein.