Targeting the dengue β-OG with serotype-specific alkaloid virtual leads

The dengue envelope β-OG pocket is a crucial hinge for mediating virus-host fusion via conformational changes in the envelope to the fusion-competent form. The β-OG pocket is a small molecule target site for inhibition of virus-host fusion. As of date, the only structure of the β-OG pocket known is of serotype 2. Studies of β-OG inhibition by small molecules primarily target viral serotype 2. Envelope and β-OG sequence alignments, reveal dissimilarities across serotypes. In light of protein sequence-structure-function correlation, sequence variations suggest serotypic variations in β-OG druggability. This, together with the fact that dengue viral proteins do have serotype-specific variations of structure and function, lead to the study of the serotype-specificity of the dengue β-OG ligand binding behaviour. β-OG druggability was compared using comparative models of envelope proteins containing the β-OG pocket in four serotypes of the dengue virus. β-OG ligand binding was found to vary with respect to hydrophobicity, hydrophilicity, hydrogen bonding, van der Waals interactions with ligands and tightness of the binding site. The study also reports serotype-specific virtual leads identified from a library of 9175 alkaloids, using a consensus docking and scoring approach. The docking algorithms of Glide SP and XP, together with the Lamarckian genetic algorithm were employed for consensus docking. For consensus scoring, the Glide empirical score was employed along with the scoring function of AutoDock. A multi-dimensional lead optimisation approach was performed for optimising affinity, ligand efficiency, lipophilic ligand efficiency, ADMET and molecular torsional strains. The study proposes the serotype-specific inhibition of the β-OG for an effective inhibition of virus-host fusion, in contrast to a pan inhibitor.