Sharma Bhanu, Rehman Md Tabish, AlAjmi Mohamed F, Shahwan Moayad, Hussain Tahir, Jaiswal Varun, Khan Mohd Azhar
Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh, India.
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
J Biomol Struct Dyn. 2024 Mar;42(5):2231-2241. doi: 10.1080/07391102.2023.2204492. Epub 2023 Apr 28.
For more than a century, the renin-angiotensin system (RAS) has been acknowledged for playing a crucial part in the physiological control of arterial pressure, as well as sodium and fluid balance. It is now generally acknowledged that one of the receptor of RAS system i.e. angiotensin type 2 receptor (AT2R) functions as a repair system during pathophysiologic circumstances and performs a significant protective role. Efforts have been made previously to design suitable agonist and antagonist molecules to potentially modulate AT2R. One of the agonists and antagonists, named C21 and EMA401, has been studied in a number of pathological conditions. Additionally, a wide panel of single nucleotide polymorphisms (SNPs) has been reported for AT2R, which might potentially affect the efficacy of these molecules. Therefore, computational investigations have been carried out to analyze all the SNPs (1151) reported in NCBI to find potential SNPs affecting the active site of AT2R, as this domain is still unexplored. Structures of these polymorphic forms were modeled, and drug interaction studies with C21 and EMA401 were carried out. The two mutants (rs868939201 and rs1042852794) that significantly affect the binding affinity as that of the wild type were subjected to molecular dynamics simulations. Our analysis of native and mutant AT2R and their complexes with C21 and EMA401 indicated that the occurrence of these mutations affects the conformation of the protein and has affected the binding of these ligand molecules. The study's findings will aid in the development of better, more versatile medications in the near future, and also and studies might be planned in accordance with recent findings.Communicated by Ramaswamy H. Sarma.
一个多世纪以来，肾素-血管紧张素系统（RAS）在动脉血压的生理调节以及钠和液体平衡方面发挥着关键作用，这一点已得到公认。现在人们普遍认为，RAS系统的一种受体，即血管紧张素2型受体（AT2R）在病理生理情况下发挥修复系统的作用，并具有重要的保护作用。此前人们已努力设计合适的激动剂和拮抗剂分子，以潜在地调节AT2R。其中一种激动剂和拮抗剂，名为C21和EMA401，已在多种病理条件下进行了研究。此外，还报道了大量关于AT2R的单核苷酸多态性（SNP），这些多态性可能会影响这些分子的疗效。因此，已开展计算研究，分析NCBI中报道的所有SNP（1151个），以寻找影响AT2R活性位点的潜在SNP，因为该结构域仍未被探索。对这些多态形式的结构进行了建模，并开展了与C21和EMA401的药物相互作用研究。对两个与野生型相比显著影响结合亲和力的突变体（rs868939201和rs1042852794）进行了分子动力学模拟。我们对天然和突变型AT2R及其与C21和EMA401的复合物的分析表明，这些突变的发生影响了蛋白质的构象，并影响了这些配体分子的结合。该研究结果将有助于在不久的将来开发出更好、更通用的药物，并且可能会根据最新发现规划进一步的研究。由拉马斯瓦米·H·萨尔马传达。
