{"doi":"10.1002/ange.202217809","title":"Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors","abstract":"<jats:title>Abstract</jats:title><jats:p>Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of <jats:italic>gluco</jats:italic> and <jats:italic>manno</jats:italic> iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the <jats:italic>gauche,gauche</jats:italic> side chain conformations are 6‐ to 10‐fold more potent than isosteric compounds with the <jats:italic>gauche,trans</jats:italic> conformation; a <jats:italic>manno</jats:italic>‐configured iminosugar with the <jats:italic>gauche,gauche</jats:italic> conformation is a 27‐fold better inhibitor than 1‐deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. The demonstration that inhibitor side chain preorganization can favorably impact glycosidase inhibition paves the way for improved inhibitor design through conformational preorganization.</jats:p>","journal":"Angewandte Chemie","year":2023,"id":680792,"datarank":0.4493598410330987,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.0,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":867229,"name":"Ande Chennaiah","orcid":"0000-0002-7599-894X","position":1,"is_corresponding":false},{"id":53135,"name":"Kelley W. Moremen","orcid":"0000-0003-1768-582X","position":2,"is_corresponding":false},{"id":262345,"name":"David Crich","orcid":"0000-0003-2400-0083","position":3,"is_corresponding":false},{"id":867228,"name":"Po‐Sen Tseng","orcid":"0000-0003-2860-5725","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Influence of Side Chain Conformation on the Activity of Glycosidase Inhibitors","abstract":"<jats:title>Abstract</jats:title><jats:p>Substrate side chain conformation impacts reactivity during glycosylation and glycoside hydrolysis and is restricted by many glycosidases and glycosyltransferases during catalysis. We show that the side chains of <jats:italic>gluco</jats:italic> and <jats:italic>manno</jats:italic> iminosugars can be restricted to predominant conformations by strategic installation of a methyl group. Glycosidase inhibition studies reveal that iminosugars with the <jats:italic>gauche,gauche</jats:italic> side chain conformations are 6‐ to 10‐fold more potent than isosteric compounds with the <jats:italic>gauche,trans</jats:italic> conformation; a <jats:italic>manno</jats:italic>‐configured iminosugar with the <jats:italic>gauche,gauche</jats:italic> conformation is a 27‐fold better inhibitor than 1‐deoxymannojirimycin. The results are discussed in terms of the energetic benefits of preorganization, particularly when in synergy with favorable hydrophobic interactions. 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