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.