In Silico Approach For Detection Of The Effect Of UGT1A1 Polymorphisms On Telmisartan Response

Abstract

Hypertension is a cardiovascular disease that manifests itself with a continuous increase in systemic arterial blood pressure and can lead to serious complications over time. It is estimated that 37% of hypertensive patients receive treatment and one-third of them are under control. Telmisartan is an angiotensin receptor blocker used in the treatment of hypertension. Uridine 5'-diphospho-glucuronyltransferase 1 (UGT1A1) gene encodes the Uridine 5'-diphospho-glucuronyltransferase (UGT) enzyme and metabolizes the telmisartan. Single nucleotide polymorphisms cause amino acid, protein structure, and function to change. These changes affect the drug response and therapy. Polymorphisms of the UGT1A1 gene (rs4148323, rs28934877) cause telmisartan resistance. In this study, the SWISS-MODEL database and Chimera 1.15 ver. Programs were used to create homology models. The HOPE database was used to calculate the damage of mutation on protein structure and show the mutation effects on protein. The HDock server was used to demonstrate interactions between telmisartan and wild-type protein and, mutant type protein. It was detected that the mutant residue of UGT1A1 (rs4148323) is located in an important domain for protein activity. Mutation might disturb the protein function. rs28934877 was detected that this mutation is probably damaging to the protein. These mutations cause the loss of interactions and affect the drug response. By docking analysis, Telmisartan drug interactions were shown between wild and mutant types protein Possible drug conformation is designed for the effective treatment of patients carrying the common mutation.