Receptor-Guided De Novo Design of Dengue Envelope Protein Inhibitors

Inhibitor design associated with the dynamics of dengue envelope protein at pre-fusion stage is a prominent strategy to interfere fusion transition of dengue virus with the host cell membrane. Receptor-guided de novo inhibitors were designed based on the knowledge of co-crystallized detergent, β-octyl glucoside. Pharmacophore features distribution showed the preference of aromatic groups with H bonding features connected to aliphatic bulky group as the skeleton for inhibitor design. Molecular dynamic simulations revealed (2R)-2-[(6-amino-1-oxohexan-2-yl)amino]-4-[6-(4-phenylpiperidine-1-yl)-1,2-benzoxazol-3-yl]butanoate as the probable binder which developed extensive conservative interactions despite the local pocket residues movements especially from kl β-hairpin, the key structural unit for initiating conformational changes required for fusion transition. The electronic and hydrophobic potentials also indicated that butanoate molecule as the initial lead for envelope protein inhibitors.