Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan-173229, Himachal Pradesh, India.
School of Electrical and Computer Science Engineering, Shoolini University of Biotechnology and Management Sciences, Solan-173229, Himachal Pradesh, India.
Curr Comput Aided Drug Des. 2021;17(7):927-935. doi: 10.2174/1573409916666201023113709.
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 are associated with AT1R and few of them were studied and found to be associated with the diseases and drug efficacy. Although it is a very important receptor most of the polymorphisms (SNPs) were not studied for their implications in diseases. A huge number of polymorphisms are reported in the databases for AT1R, which provide an avenue to explore these polymorphisms for their implications in protein structure, function and drug efficacy.
In the current study, all the SNPs (10234) reported in NCBI were analyzed and SNPs that 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.
The 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) show considerably less binding affinities in the 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), show 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 the case of these two ARBs.
The outcome of the study will help in designing better drugs in the near future with broader spectrum. Furthermore, in vitro and in vivo studies can be designed according to the current results.
血管紧张素 II 型 1 型受体（AT1R）是肾素-血管紧张素系统（RAS）的主要组成部分，当血管紧张素 II（ANG II）与之结合时，它会被激活。AT1R 有助于维持渗透平衡和血压调节。大量与 AT1R 相关的多态性与少数已被研究并发现与疾病和药物疗效相关的多态性有关。尽管它是一种非常重要的受体，但大多数多态性（SNP）并未因其对疾病的影响而得到研究。AT1R 的数据库中报告了大量多态性，为探索这些多态性对蛋白质结构、功能和药物疗效的影响提供了途径。
在本研究中，分析了 NCBI 中报告的所有 SNP（10234），并确定了对蛋白质结构和药物相互作用重要的 SNP。对这些多态形式的结构进行建模，并进行了计算机药物相互作用研究。
与报道的病例相吻合的是，与多态性的相互作用研究的结果。AT1R 的两个 SNP 突变结构，即 rs780860717（G288T）、rs868647200（A182C），在所有血管紧张素受体阻滞剂（ARBs）的情况下显示出相当低的结合亲和力。因此，这些多态性可能对这些 ARBs 的疗效较低。其他突变结构 rs12721226（A163G）、rs749234826（A292G）、rs775810028（A87G），在 Eprosartan 的情况下显示出增加的结合亲和力，而大多数突变结构比野生型 AT1R 对 Telmisartan 显示出增加的结合亲和力。同样，这些多态性在这两种 ARB 的情况下可能显示出更高的疗效。
该研究的结果将有助于在不久的将来设计更广泛谱的更好的药物。此外，根据目前的结果，可以设计体外和体内研究。
