Bimolecular modeling and simulation of antagonist binding to the alpha‐1A adrenergic receptor

Abstract

Benign prostatic hyperplasia (BPH), which is a noncancerous enlargement of the prostate, currently affects 70% of men 60–69 years old, and 80% of men 70 years and older. By 2030, BPH incidence is predicted to increase based on the aging US population, and estimates suggest 20 million men 65 years and older will be diagnosed with BPH. BPH symptoms include frequent urination, difficulty initiating, maintaining, or a weak stream during urination, as well as inability to urinate or loss of bladder control. α1‐Adrenergic receptors (α1‐ARs), and particularly the α1A‐subtype, are highly expressed in prostate smooth muscle cells and mediate contraction. Clinically, α1‐AR antagonists, or α1‐blockers, are the primary treatment BPH with lower urinary tract symptoms (LUTS), including tamsulosin, touted as an α1A‐subtype selective antagonist. Here, our goal was to understand the molecular forces governing α1‐blocker binding to α1‐ARs to better understand α1‐blocker pharmacology. We have developed a homology model of α1‐antagonist binding to the α1A‐AR to identify essential molecular parameters that can be exploited for structure‐based drug design. Through homology modeling, docking, and molecular dynamics simulation, our preliminary model complex suggests for the first time 1) the burial of the terminal aromatic core within the hydrophobic pocket α1A‐AR and 2) the salt bridge interaction between its charged ammonium group with ionized aspartate are essential for ligand binding. This finding provides invaluable insight into design of the next generation, subtype‐specific of novel a1‐blockers.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.