Modeling and Molecular Dynamics Studies of Flavone-DENV E-3 Protein-SWCNT Interaction at the Flavonoid Binding Sites

Abstract

The DENV virus circulates freely in endemic regions and causes dengue disease. The vectors are Aedes aegypti and Aedes albopictus. The difficulties inherent in the nature of the DENV virus, its epidemiology, and its increasing incidence in recent years have led to the development of viable alternatives in the search for effective solutions for the treatment of this severe disease. Flavones such as tropoflavin, baicalein, and luteolin have anti-DENV activity. Molecular docking studies were performed between the flavones tropoflavin, baicalein, and luteolin and the DENV E-3 protein. Flavone-DENV E-3 complex interactions were analyzed at the flavonoid binding sites domain I of the B chain and domain II of the A chain reported in the literature. H-bond, π-π stacking, and π-cation interactions between flavones and the DENV E-3 protein at different binding energies were evaluated. Molecular dynamics studies for these interactions were performed to determine the molecular stability of the Flavone-DENV E-3 complexes. I also present here the results of the molecular interactions of the Flavone-DENV E-3-SWCNT complex. Due to recent advances in nanotechnology and their physicochemical properties, the utilization of nanoparticles such as SWCNT has increased in antiviral drug delivery.

Keywords: DENV E-3 protein; Flavone—DENV E-3 interactions; SWCNT–flavonoids; anti-DENV drugs; antiviral pharmacology; docking molecular; flavones; molecular dynamic simulation; nanomedicine; non-covalent interaction.

Figure 1

DENV virus types in Americas region in 2023 [3].

Figure 2

DENV E-3 protein.

Figure 3

Molecular docking phases for Flavone—DENVE-3 complex interaction.

Figure 4

H-bond interaction of residues GlyA:152, ArgA:2 and π-π stacking interaction of residue ArgB:99 with tropoflavin. ΔG = −7.0 kcal/mol.

Figure 5

H-bond interactions between luteolin and residues LysA:245, HisA:242, and LysA:239. ΔG = −5.19 kcal/mol.

Figure 6

H-bond and π-cation interactions between baicalein and residues GluB:44, GlyB:28 and LysA:244. ΔG = −6.4 kcal/mol.

Figure 7

The rotatable bonds in the SWCNT.

Figure 8

SWCNT positions on the DENV E-3 surface.

Figure 9

SWCNT—DENV E-3 interaction. ΔG = −11.77 kcal/mol.

Figure 10

H-bond interaction with TrpB:229 in the tropoflavin–DENV E-3—SWCNT complex. ΔG = −6.8 kcal/mol. 3D.

Figure 11

Two-dimensional diagram of H-bond interaction in tropoflavin–DENV E-3—SWCNT complex. Carbon atom of SWCNT is observed (blue).

Figure 12

Three-dimensional diagram of π-π stacking and H-bond interactions with TrpB:229 and GlnB:120 in baicalein–DENV E-3—SWCNT complex. ΔG = −6.99 kcal/mol.

Figure 13

Two-dimensional diagram of π-π stacking and H-bond interaction in baicalein–DENVE-3—SWCNT complex. SWCNT is observed (blue).

Figure 14

Three-dimensional diagram of H-bond interactions with LysB:58 and CysB:121 in luteolin–DENV E-3—SWCNT complex. ΔG = −6.8 kcal/mol.

Figure 15

Two-dimensional diagram of H-bond interaction in luteolin–DENV E-3—SWCNT complex. SWCNT is observed (blue).

Figure 16

DENV E-3—Tropoflavin protein simulation trajectory with 100 ns. (a) RMSD protein. (b) RMSF protein. (c) DENV E-3—Tropoflavin interactions during the simulation trajectory. (d) Histogram of the DENV E-3—Tropoflavin interaction fraction H-bonds, hydrophobic, Ionic, Water bridge.

Figure 17

DENV E-3—Baicalein protein simulation trajectory with 100 ns. (a) RMSD protein. (b) RMSF protein. RMSD protein. (b) RMSF protein. (c) DENV E-3—Baicalein interactions during the simulation trajectory. (d) Histogram of DENV E-3—Baicalein interaction fraction H-bonds, hydrophobic, Ionic, Water bridge.

Figure 18

DENV E-3―Luteolin protein simulation trajectory with 100 ns. (a) RMSD protein. (b) RMSF protein. (c) DENV E-3―Luteolin interactions during the simulation trajectory. (d) Histogram of the DENV E-3―Luteolin interaction fraction H-bonds, hydrophobic, Ionic, Water bridge.

Figure 19

Apo DENV E-3 protein at 100 ns. (a) RMSD (b) RMSF.

Figure 20

DENV E-3―Luteolin protein simulation trajectory with 500 ns. (a) RMSD protein. (b) RMSF protein. (c) DENV E-3―Luteolin interactions during the simulation trajectory. (d) Histogram of the DENV E-3―Luteolin interaction fraction H-bonds, hydrophobic, Ionic, Water bridge.