In silico Approach for Exploring the Role of AT1R Polymorphism on its Function, Structure and Drug Interactions

Abstract

Background: AT1R (Angiotensin II type 1 receptor) is the main component of RAS (renin-angiotensin system) system which activates when ANG II (angiotensin II) binds to it. AT1R helps in maintaining osmotic homeostasis and blood pressure regulation. A huge number of polymorphism is associated with AT1R and few of them were studied and found to be associated with the diseases and drug efficacy. Although it is very important receptor but most of the polymorphisms (SNPs) were not studied for their implications in diseases. Huge number of polymorphisms is reported in the databases for AT1R which provide an avenue to explore these polymorphisms for their implications in protein structure, function and drug efficacy. Methods: In the current study all the SNPs (10234) reported in NCBI were analyzed and SNPs which were important in protein structure and drug interactions were identified. Structures of these polymorphic forms were modeled and in silico drug interaction studies were carried out. Results: Result of the interaction studies with polymorphism was in correlation with the reported case. Two SNP mutated structures of AT1R i.e. rs780860717 (G288T), rs868647200 (A182C) shows considerably less binding affinities in case of all angiotensin receptor blockers (ARBs). As a result these polymorphisms may show less efficacy toward these ARBs. The other mutated structures rs12721226 (A163G), rs749234826 (A292G), rs775810028 (A87G) shows increased binding affinities in case of Eprosartan and most of the mutated structures shows increased binding affinity toward Telmisartan than the wild type AT1R. Similarly, these polymorphisms may show increased efficacy in case of these two ARBs. Conclusion: The outcome of the study will help in designing better drugs in near future with broader spectrum. Furthermore in vitro and in vivo studies can be designed according to current results.