{"doi":"10.17615/83jp-9g80","title":"Enantiomer Discrimination Illustrated by the High Resolution Crystal Structures of Type 4 Phosphodiesterase †","abstract":"Type 4 phosphodiesterase (PDE4) inhibitors are emerging new treatment for a number of disorders including asthma and chronic obstructive pulmonary disease. Here we report the biochemical characterization on the second generation inhibitor (+)-1 (L-869298, IC50 = 0.4 nM) and its enantiomer (−)-1 (L-869299, IC50 = 43 nM), and their co-crystal structures with PDE4D at 2.0 Å resolution. In spite of the 107-fold affinity difference, both enantiomers interact with the same sets of residues in the rigid active site. The weaker (−)-1 adopts an unfavorable conformation in order to preserve the pivotal interactions between the Mg-bound waters and N-oxide of pyridine. These structures support a model in which inhibitors are anchored by the invariant glutamine at one end and the metal-pocket residues at another end. This model provides explanation for most of the observed structure-activity relationship and the metal ion dependency of the catechol-ether based inhibitors and should facilitate their further design.","journal":"UNC Libraries","year":2020,"id":139554,"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":0.956,"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":602323,"name":"Zheng Huang","orcid":"0009-0009-2607-5610","position":1,"is_corresponding":false},{"id":602324,"name":"Dwight Macdonald","orcid":"0000-0002-6838-7905","position":2,"is_corresponding":false},{"id":603037,"name":"Renée Aspiotis","orcid":null,"position":3,"is_corresponding":false},{"id":519448,"name":"Howard Robinson","orcid":"0000-0001-7523-4678","position":4,"is_corresponding":false},{"id":451721,"name":"Huanchen Wang","orcid":"0000-0003-2701-7155","position":5,"is_corresponding":false},{"id":603038,"name":"Qing Huai","orcid":null,"position":6,"is_corresponding":false},{"id":602325,"name":"Yingjie Sun","orcid":"0000-0002-1885-1693","position":7,"is_corresponding":false},{"id":519449,"name":"Hengming Ke","orcid":"0000-0001-8864-7279","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:10.185988Z","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":[]}