Targeting a conserved pocket (n-octyl-β-D–glucoside) on the dengue virus envelope protein by small bioactive molecule inhibitors

Dengue virus enters the cell by receptor-mediated endocytosis followed by a viral envelope (DENVE) protein-mediated membrane fusion. A small detergent molecule n-octyl-β-D-glucoside (βOG) occupies the hydrophobic pocket which is located in the hinge region plays a major role in the rearrangement. It has been reported that mutations occurred in this binding pocket lead to the alterations of pH threshold for fusion. In addition to this event, the protonation of histidine residues present in the hydrophobic pocket would also impart the conformational change of the E protein evidence this pocket as a promising target. The present study identified novel cinnamic acid analogs as significant blockers of the hydrophobic pocket through molecular modeling studies against DENVE. A library of seventy-two analogs of cinnamic acid was undertaken for the discovery process of DENV inhibitors. A Molecular docking study was used to analyze the binding mechanism between these compounds and DENV followed by ADMET prediction. Binding energies were predicted by the MMGBSA study. The Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. The compounds CA and SCA derivatives have been tested against HSV-1 & 2 viruses. From the computational results, the compounds CA1, CA2, SCA 60, SCA 57, SCA 37, SCA 58, and SCA 14 exhibited favorable interaction energy. The compounds have in-vitro antiviral activity; the results clearly indicate that the compounds showed the activity against both the viruses (HSV-1 & HSV-2). Our study provides valuable information on the discovery of small molecules DENVE inhibitors.Communicated by Ramaswamy H. Sarma.