Identification of a Conserved Allosteric Site Between the Alphaviruses VEEV and Chikungunya via Bioinformatic Sequence Analysis and Structural Modeling

Abstract Alphaviruses such as the Venezuelan Equine Encephalitis Virus (VEEV) and Chikungunya Virus (CHIKV) represent a significant public health threat. Current therapeutic strategies, often targeting hyper-variable viral active sites, face challenges with resistance and specificity. This work was based on a five-year hypothesis: that a more universal vulnerability might exist in a conserved, structurally critical allosteric site. Through an extensive, multi-year process of 1D sequence analysis and subsequent manual screening of 3D structural models, a single conserved allosteric pocket between VEEV and CHIKV has been identified. The site exhibits an extraordinary degree of structural identity, quantified by a Root-Mean-Square Deviation (RMSD) of only 0.210 Å for the backbone atoms of the central residue. This pocket represents a high-potential target for the development of broad-spectrum pan-alphaviral inhibitors. This study presents the computational evidence for this finding and underscores the urgent need for experimental validation.