Identification of natural antiviral drug candidates against Tilapia Lake Virus: Computational drug design approaches

Abstract

Tilapia Lake Virus (TiLV) is a disease that affects tilapia fish, causing a high rate of sudden death at any stage in their life cycle. Unfortunately, there are currently no effective antiviral drugs or vaccines to prevent or control the progression of this disease. Researchers have discovered that the CRM1 protein plays a critical function in the development and spreading of animal viruses. By inhibiting CRM1, the virus's spread in commercial fish farms can be suppressed. With this in mind, this study intended to identify potential antiviral drugs from two different tropical mangrove plants from tropical regions: Heritiera fomes and Ceriops candolleana. To identify promising compounds that target the CRM1 protein, a computer-aided drug discovery approach is employed containing molecular docking, ADME (absorption, distribution, metabolism and excretion) analysis, toxicity assessment as well as molecular dynamics (MD) simulation. To estimate binding affinities of all phytochemicals, molecular docking is used and the top three candidate compounds with the highest docking scores were selected, which are CID107876 (-8.3 Kcal/mol), CID12795736 (-8.2 Kcal/mol), and CID12303662 (-7.9 Kcal/mol). We also evaluated the ADME and toxicity properties of these compounds. Finally, MD simulation was conducted to analyze the stability of the protein-ligand complex structures and confirm the suitability of these compounds. The computational study demonstrated that the phytochemicals found in H. fomes and C. candolleana could potentially serve as important inhibitors of TiLV, offering practical utility. However, further in vivo investigations are necessary to investigate and potentially confirm the effectiveness of these compounds as antiviral drugs against the virus TiLV.

Fig 1. The surface area of the active pockets of CRM1 (selected four) was calculated using the CASTp server.

All the active sites i.e., AS1, AS2, AS3 & AS4 with their corresponding amino acids are depicted respectively in light blue, deep blue, yellow and red.

Fig 2. The interaction between the chemical CID107876 and CRM1.

(A). The 3D interaction is shown on the left of the protein ligands, while the 2D interaction is shown on the right (B).

Fig 3. The interaction among chemical CID12795736 and CRM1.

(A). The 3D interaction is shown on the left of the protein ligands, while 2D interaction is shown on the right (B).

Fig 4. Interaction among chemical CID12303662 and CRM1.

(A). The 3D interaction is shown on the left of the protein ligands, while 2D interaction is shown on the right (B).

Fig 5. Construction of a three-dimensional grid encompassing a molecule of interest.

Subsequently, the steric (shape) and electrostatic characteristics are computed at each grid point using the Comparative Molecular Field Analysis (CoMFA) technique. This analysis is performed for a set consisting of the three chosen compounds.

Fig 6. RMSD values obtained from the Cα atoms of CRM1 (represented by blue curves).

Naturally occurring compounds were analyzed over a 100 ns simulation time. Specifically, the RMSD values for CID107876 are depicted as brown curves, CID12795736 as violet curves, CID6917907 as red curves and CID12303662 as green curves.

Fig 7. RMSF values extracted from the protein residue index Cα atoms of the complex structure.

Values shown include CID107876 (brown), CID12795736 (violet), CID12303662 (green), CID6917907 (red), and CRM1 (blue) regarding 100 ns of simulation time.

Fig 8. Stacked bars of the contact mapping of CRM1 with potential natural phytochemicals.

Illustrated here are (A) CID107876; (B) CID 12795736; and (C) CID 12303662 determined from simulations trajectory of 100 ns.

Fig 9. Ligand torsions plots.

These provide a summary of how each RB in the ligand underwent conformational changes throughout the entire simulation trajectory (from 0 to 100 ns).

Fig 10. MM/GBSA calculation from the selected three compounds.

Binding free energy for each of the three compounds in association with CRM1 is given in kcal/mol and in Coulombs. Calculated No Strain binding values (NS) for each pair are also shown in both kcal/mol and Coulombs.

Fig 11. Solvent accessible surface area (SASA) of the protein–ligand complex.

These values were calculated from the compounds (A) CID: 107876, (B) CID: 12303662, and (C) CID: 12795736 until 100 ns simulation.