Identification of potential VP40 inhibitor of Marburg virus through molecular docking, pharmacokinetic analysis and molecular dynamics simulation

Abstract

West Africa has been experiencing a resurgence of Marburg virus disease (MVD), a zoonotic pathogen that causes severe hemorrhagic fever in both humans and primates. Regretfully, there are not any effective medications on the market right now. The binding interactions between MARV VP40, a protein essential to viral replication, and a commercial medication, estradiol benzoate, and a natural substance, procyanidin, were examined in this work. Ten hydrogen bonds and hydrophobic interactions with important residues (Ala316, Val317, Lys230, Glu89, Asn87) stabilized procyanidin's superior binding affinity (- 11.3 kcal/mol) over estradiol benzoate (- 8.9 kcal/mol), according to molecular docking. With a lower radius of gyration (1.94 nm) and RMSD (0.28 nm) than estradiol benzoate (RMSD: 0.37 nm, Rg: 1.97 nm), procyanidin formed a more stable complex, according to molecular dynamics simulations conducted over 200 ns. Additionally, procyanidin showed decreased solvent accessibility and increased intermolecular hydrogen bonding (average 3.50 bonds), suggesting stronger binding. Procyanidin's superior drug-likeness, decreased cardiotoxicity, and decreased carcinogenicity potential were all shown by ADMET analysis. Its higher binding energy (- 57.82 KJ/mol) was further validated by free energy calculations (MM-PBSA). According to these results, procyanidin, a natural substance shows promise as an antiviral medication against MARV targeting its VP40 protein.

Keywords: MARV VP40; Medicinal plants; Molecular docking; Molecular dynamics simulation; Procyanidin.

Fig. 1

(a) protein-ligand interaction, 2D diagram and binding affinity of natural compound Procyanidin. (b) protein-ligand interaction, 2D diagram and binding affinity of commercial compound estradiol benzoate.

Fig. 2

(a) Calculations of backbone RMS deviations for each trajectory of VP40 with natural compound Procyanidin run1 (Violet), run2 (Magenta), and run3 (Green) and commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations. (b) Calculations of backbone RMS fluctuation for each trajectory of VP40 with natural compound Procyanidin run1(Violet), run2 (Magenta), and run3 (Green) and commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations. (c) Fluctuating residue of protein when attached to procyanidin. (d) Fluctuating residue of protein when attached to estradiol benzoate.

Fig. 3

(a) The radius of gyration measuring compactness of the envelope protein during 200 ns MD simulations. lower gyrations were observed from the initial conformations till the end of the simulations for natural compound run1 (Violet), run2 (Magenta), and run3 (Green) and higher gyration in commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations. (b) Intermolecular H-bonding interactions of the protein–ligand complexes corresponding to 200 ns MD simulations. Lesser number of H-bonds were found in commercial compound estradiol benzoate (black) and higher in natural compound Procyanidin (red).

Fig. 4

(a) SASA plot analysis corresponding to 200 ns MD simulations of natural compound Procyanidin run1 (Violet), run2 (Magenta), and run3 (Green) and higher gyration in commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations. (b) Average SASA plot analysis corresponding to 200 ns MD simulations of natural compound Procyanidin run1 (Violet), run2 (Magenta), and run3 (Green) and higher gyration in commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations.

Fig. 5

(a) 2D projections of the principal eigenvectors (PC1 and PC2) of commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations. (b) Principal component analysis (PCA) and free energy landscape (FEL) models of the commercial compound estradiol benzoate run1 (Red), run2 (Yellow), and run3 (Orange) from the initial position till 200 ns MD simulations.

Fig. 6

(a) 2D projections of the principal eigenvectors (PC1 and PC2) of natural compound Procyanidin run1 (Violet), run2 (Magenta), and run3 (Green) from the initial position till 200 ns MD simulations. (b) Principal component analysis (PCA) and free energy landscape (FEL) models of the natural compound Procyanidin run1 (Violet), run2 (Magenta), and run3 (Green) from the initial position till 200 ns MD simulations.