"Molecular Docking and Dynamic Studies of Amide Derivatives from Cinnamic Acid with Potential Anti-Dengue Virus Activity"

Abstract

Dengue, classified as a neglected tropical disease and transmitted by Aedes mosquitoes, remains a significant global health challenge, often evolving into severe clinical manifestations such as hemorrhagic fever. Despite its widespread impact, no antiviral therapy has been approved to date, highlighting the urgent need for effective and accessible treatment options. In the present work, computational analysis is performed on an in-house library of easily synthesized caffeic acid phenethyl ester analogs, which exhibit potential activity against the viral envelope (E) protein, a critical mediator of dengue virus entry and membrane fusion. Among them, LQM778 demonstrated consistent stability within the protein-ligand complex during molecular dynamics simulations. This finding provides a foundation for in vitro studies and future structural optimizations that could transform the landscape of antiviral development against dengue.

Keywords: dengue; molecular dynamics; virtual screening; viruses.

Figure 1

Country reporting cases (Figure obtained April 2025).^{[ 48 ]}

Figure 2

Dengue cases affecting countries throughout the Americas over time (data obtained April 2025).^{[ 49 ]}

Figure 3

Flavivirus polyprotein. The flavivirus genome encodes a polyprotein that is cleaved into different functional proteins. Different proteases perform specific cleavages in polyproteins.

Figure 4

Dimer domains of pE. A) Folding of glycoprotein E (PDB:1OKE). B) Important amino acids at the β‐OG site. C) Site search by SiteFinder.

Figure 5

Structural overlay of protein E (1OKE yellow) (1OAN purple). RMSD global top. The RMSD of the lower part of the β‐OG site.

Figure 6

A) Structure of CAPE. B) Chemical structures of the compounds used in molecular docking, as well as the base scaffold of the LQM 700 series. C) Synthesis outline for LQM778.

Figure 7

Main Interactions of LQM778 with the 4 serotypes of DENV.

Figure 8

A) GNM of pE with the presence of a N‐BOG ligand bound in the βOG pocket. B) GNM of pE with the presence of LQM778 bound in the βOG pocket.

Figure 9

A,D,G) RMSD of the complex simulation of DENV1 pE and the N‐βOG ligand (yellow), LQM778 with CF₃ groups oriented “down” (red), LQM778 with CF₃ groups oriented “up” (blue), and the DENV1 pE APO state (black). B,E,H) RMSF of the complexes pE and ligands N‐βOG (yellow), LQM778 CF₃ “down” (red), and LQM778 CF₃ “up” (blue). C,F,I) Number of hydrogen bonds between pE and the ligands N‐βOG (yellow), LQM778 CF₃ “down” (red), and LQM778 CF₃ “up” (blue).

Figure 10

A) Important interactions of 3D LQM778 in the E protein–ligand complex at 200 ns of simulation. B) Occupancy of the pocket in the protein by the ligand. C) 2D interactions between the E protein and the ligand LQM778.

Figure 11

A) Identity matrix of 4 Dengue envelope protein serotypes in the β‐OG pocket. B) Similarity matrix of 4 Dengue envelope protein serotypes in the β‐OG pocket. C) Alignment of 4 serotypes of the dengue E protein; the β‐OG pocket is shown in blue, and the glycosylation sites are shown in purple, N67, and N153.

Figure 12

Superposition of the trimeric and dimeric forms of the DENV1 envelope protein obtained from the last 100 ns of the molecular dynamics simulation.