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

TL;DR

This study identifies new druggable pockets on the surface of the dengue virus's protein E in its native form, offering potential targets for antiviral drug development.

Contribution

The study reveals novel druggable pockets on the biological assemblies of DENV-2’s protein E, not previously observed in isolated dimers.

Findings

Several druggable pockets were identified on the native oligomeric states of protein E.

Key residues like Lys291, Lys295, and Pro384 are located in these pockets and are involved in host receptor interactions.

Residues Glu172, Thr180, Thr303, and Glu383 were found in druggable pockets, suggesting their role in pharmacophore modeling.

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.

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