Computational design of a sulfoglucuronide derivative fitting into a hydrophobic pocket of dengue virus E protein.

We performed first-principles calculations based on the ab initio fragment molecular orbital method on dengue virus envelope protein with a hydrophobic ligand, octyl-ß-D-glucose to develop an entry inhibitor. As several polar amino acid residues are present at the edge of the pocket, the glucose moiety was chemically modified with hydrophilic groups. Introduction of both sulfated and carboxylated groups on glucose enhanced not only binding affinity to the protein but also inhibition of dengue virus entry. Octyl-2-O-sulfo ß-D-glucuronic acid may serve as a molecular probe to study the dengue virus entry process.