Structure-based screening and validation of potential dengue virus inhibitors through classical and QM/MM affinity estimation

Abstract

The recurrent outbreaks of dengue virus around the globe represent a huge challenge for governments and public health organizations. With the rapid growth and ease of transportation, dengue disease continues to spread, placing more of the world population under constant threat. Despite decades of research efforts, no effective small molecule antivirals are available against dengue virus. With the efficacy of the recently developed vaccine to be determined, there is an urgent unmet need for small molecule dengue virus treatments. In the current study, we employed state-of-the-art molecular modelling simulations to identify novel inhibitors of the dengue virus envelope protein. The binding modes of all compounds within the conserved β-OctylGlucoside (β-OG) pocket were studied using a combination of docking, molecular dynamics simulations and binding free energy calculations. Here, we describe ten new compounds that significantly reduce production of dengue virus as determined using standard cell-based virological assays. Moreover, we present a comprehensive structural analysis of the identified hits, focusing on their electrostatic and lipophilic binding energy contributions. Finally, we highlight the effect of the desolvation penalty in limiting the activity of some of these compounds. The data presented here paves the way toward rationally designing selective and potent novel inhibitors against dengue virus.

Keywords: Binding energy; Dengue virus; Envelope protein; Molecular dynamics; QM/MM.