Computational analysis and validation of UGT1A1/4 missense variants impacting tecovirimat metabolism in monkeypox patients.

INTRODUCTION

Single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes can significantly impact a patient's response to medication. Uridine diphosphate glucuronosyltransferase 1 family A1 and A4 (UGT1A1/4) are crucial enzymes for metabolizing tecovirimat, the first oral antiviral drug approved for treating the monkeypox virus.

METHODS

This study used a comprehensive in-silico workflow to assess the deleterious effects of 842 missense mutations and 308 SNPs in the non-coding regions of the UGT1A1 gene, alongside 700 missense mutations and 324 SNPs in the non-coding regions of the UGT1A4 gene. An ensemble of in-silico prediction, structural modelling, and docking tools was employed.

RESULTS

We identified six missense variants that may compromise the structural integrity and function of the UGT1A1/4 enzymes. Specifically, the UGT1A1 SNPs G308R, P356T and G374S, while in UGT1A4 the SNPs G309R, P357T and G375S, were predicted to be the most harmful missense SNPs.

DISCUSSION: These mutations could affect drug-enzyme binding, potentially altering tecovirimat's therapeutic efficacy.