Structure of Human Phosphodiesterase 5A1 Complexed with Avanafil Reveals Molecular Basis of Isoform Selectivity and Guidelines for Targeting α-Helix Backbone Oxygen by Halogen Bonding
Journal
Journal of medicinal chemistry
Journal Volume
63
Journal Issue
15
Pages
8485
Date Issued
2020
Author(s)
Abstract
Phosphodiesterase 5A1 (PDE5) is a key target for treating cardiovascular diseases and erectile dysfunction. Here, we report the crystal structure of PDE5 complexed with the sole second generation drug avanafil. Analysis of protein-drug interactions revealed the structural basis of avanafil's superior isoform selectivity. Moreover, a halogen bonding was observed between avanafil and a backbone carbonyl oxygen of an adjacent α-helix, whose contribution to inhibitory potency illustrates the feasibility of exploiting α-helix backbone in structure-based drug design.
Subjects
ERECTILE DYSFUNCTION; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; SWISS-MODEL; INHIBITORS; DISCOVERY; REFINEMENT; BINDING; SUBSTRATE; FEATURES
SDGs
Other Subjects
avanafil; halogen; isoenzyme; oxygen; phosphodiesterase; phosphodiesterase I; phosphodiesterase V; phosphodiesterase V alpha 1; phosphodiesterase VI; phosphodiesterase XI; unclassified drug; avanafil; isoprotein; PDE5A protein, human; phosphodiesterase V; phosphodiesterase V inhibitor; pyrimidine derivative; alpha helix; Article; controlled study; crystal structure; drug binding site; drug design; drug potency; drug protein binding; drug selectivity; enzymatic assay; enzyme active site; enzyme structure; gene mutation; human; hydrogen bond; hydrophobicity; ligand binding; pharmacophore; practice guideline; protein conformation; protein targeting; structure activity relation; X ray crystallography; alpha helix; chemistry; drug effect; metabolism; molecular docking; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Design; Humans; Molecular Docking Simulation; Phosphodiesterase 5 Inhibitors; Protein Conformation; Protein Conformation, alpha-Helical; Protein Isoforms; Pyrimidines
Publisher
AMER CHEMICAL SOC
Type
journal article