Reading between the Chains: Surface Mapping and Druggable Pockets on the Biological Assemblies of DENV-2's Protein E.

Abstract

Dengue is a widespread arboviral infection endemic to tropical and subtropical regions, representing a major global public health concern. Although most prevalent in South America and Asia, cases have also emerged in Europe and the United States, including instances of local transmission and fatalities. The envelope protein (protein E) is a critical structural component of the viral surface and a well-established molecular target for antiviral drug discovery, owing to its essential role in viral entry. While previous studies have primarily focused on the β-OG pocket within isolated protein E dimers, the mature virion features a complex icosahedral organization composed of protein E dimers adopting distinct assemblies, which might expose novel pockets not present in the dimeric forms, offering new opportunities for structure-based drug design. In this study, we employed molecular dynamics simulations and structure-based computational analyses to identify and characterize druggable pockets on the external surface of protein E in its native oligomeric states. Side chain conformational sampling revealed distinct side chain dynamics and enabled the selection of representative structures for pocket mapping. Several druggable and borderline druggable pockets were identified, including sites encompassing residues such as Lys291, Lys295, and Pro384key mediators of protein E interaction with host membrane receptors. Additionally, residues such as Glu172, Thr180, Thr303, and Glu383 were found within druggable pockets, supporting their potential inclusion in pharmacophore models. These findings offer valuable insights for pharmacophore modeling and drug repurposing initiatives.