New potential inhibitors molecules of the envelope protein from dengue virus type 2

Background. By 2024, 14.1 million cases of dengue were reported around the world, folding the amount of 2023. Dengue is an orphan disease caused by the dengue virus (DENV), and it’s transmitted by mosquitoes such as Aedes aegypti, which has one of the highest reproductive rates and is more susceptible to the DENV-2 serotype. Scientific studies indicate that the envelope protein (EP) could be inhibited avoiding the viral fusion and interrupting the replication.

Method. EP was downloaded from PDB (1OKE code) and processed using PyMOL software. The scaffold was selected by searching for active chemical structures in ChEMBL from a study of 163 molecules. Molecular docking was performed using Autodock-Vina 1.1.2. The molecules with the highest activity were 36 and 136. In molecular dynamics the molecule 136 exhibited a better affinity, binding the amino acid THR48 of EP through the pharmacophore alpha-ethylidene thiohydantoin. One thousand one hundred thirty three bioisosteres were performed using alpha-ethylidene thiohydantoin scaffold with the Zinc 20 database. The bioisosteres were bring under molecular docking and four were selected.

Results. Molecules 1104, 1101, 1154, and 872 were found with better affinity than 136, they put through to molecular docking using Autodock Vina 1.1.2. SAR analysis of molecule 1104 show greater activity due to the ketone group, which influences the coplanarity of the heterocyclic cyclopentane, making better use of the pocket of the EP catalytic site and stabilizing by forming hydrogen bonds with AL50.

Conclusions. Four novel compounds of promising activity against envelope protein of dengue virus type 2 where found.