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

Hsieh, Chao-MingChao-MingHsiehChen, Chun-YiChun-YiChenJI-WANG CHERNNEI-LI CHAN2021-03-102021-03-1020200022-2623https://scholars.lib.ntu.edu.tw/handle/123456789/551375Phosphodiesterase 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.animationERECTILE DYSFUNCTION; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; SWISS-MODEL; INHIBITORS; DISCOVERY; REFINEMENT; BINDING; SUBSTRATE; FEATURES[SDGs]SDG3avanafil; 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; PyrimidinesStructure of Human Phosphodiesterase 5A1 Complexed with Avanafil Reveals Molecular Basis of Isoform Selectivity and Guidelines for Targeting α-Helix Backbone Oxygen by Halogen Bondingjournal article10.1021/acs.jmedchem.0c00853326633962-s2.0-85089614611WOS:000562941200037https://api.elsevier.com/content/abstract/scopus_id/85089614611