{"doi":"10.17615/8hjs-9d30","title":"Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor","abstract":"Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.","journal":"UNC Libraries","year":2020,"id":142297,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9599,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":609323,"name":"Yanchen Wu","orcid":null,"position":1,"is_corresponding":false},{"id":609324,"name":"Yuzhuo Shao","orcid":null,"position":2,"is_corresponding":false},{"id":608859,"name":"Wei Cui","orcid":"0000-0002-6324-5772","position":3,"is_corresponding":false},{"id":608860,"name":"X. Zhu","orcid":"0009-0005-4206-607X","position":4,"is_corresponding":false},{"id":26150,"name":"Y. Huang","orcid":"0000-0003-1826-2749","position":5,"is_corresponding":false},{"id":608861,"name":"Z. Li","orcid":"0000-0002-8362-5617","position":6,"is_corresponding":false},{"id":608862,"name":"B. Liang","orcid":"0009-0004-9831-1655","position":7,"is_corresponding":false},{"id":609325,"name":"H.-B. Luo","orcid":null,"position":8,"is_corresponding":false},{"id":26357,"name":"P. Liu","orcid":"0000-0002-9815-8898","position":9,"is_corresponding":false},{"id":609326,"name":"YuCheng Wan","orcid":null,"position":10,"is_corresponding":false},{"id":549501,"name":"M. Huang","orcid":null,"position":11,"is_corresponding":false},{"id":437970,"name":"Junren Hou","orcid":"0009-0009-7016-707X","position":12,"is_corresponding":false},{"id":438765,"name":"Hongjiao Ke","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:31.424593Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}