Abstract
Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 -L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.
Highlights
The Angiotensin (Ang) II type 1 receptor (AT1R) is often studied due to its role in cardiovascular disease, diabetes, and, more recently, cancer [1, 2]
One potential reason a patient does not respond, or respond optimally, to an ARB is that there could be a, or many, non-synonymous single nucleotide polymorphism(s) within the agtr1 coding sequence. nsSNPs can result in altered antagonist function [6]; as we enter an era dominated by big data and likely personalized medicine, it would be ideal for a prescriber to know which therapies will interact with their target as expected in each patient
In order to obtain a model of the empty Angiotensin II type 1 receptor (AT1R), the AT1R crystal structure (PDB: 4ZUD) was modified to remove non-receptor residues and the unresolved flexible loops were added back to the receptor, a short 150 ns molecular dynamics (MD) simulation was conducted within a POPC:cholesterol (87:13 ratio) membrane to relax the structure to a ligand-free state (n = 3); the trajectory files are available at https://zenodo.org/ record/3988469#.X2pH4mhKiHu
Summary
The Angiotensin (Ang) II type 1 receptor (AT1R) is often studied due to its role in cardiovascular disease, diabetes, and, more recently, cancer [1, 2]. NsSNPs can result in altered antagonist function [6]; as we enter an era dominated by big data and likely personalized medicine, it would be ideal for a prescriber to know which therapies will interact with their target as expected in each patient. Such patient-specific knowledge can come from genetic screening coupled to robust databases linking drug affinities and effects to the genetic sequence of the target receptor(s). If there is no previous data, there should be a mechanism allowing rapid assessment of which drugs are appropriate for a given patient, such as in silico modeling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
