title: Discovery of novel PTP1B inhibitors via pharmacophore-oriented scaffold hopping from Ertiprotafib.
abstract: An integrated molecular design strategy combining pharmacophore recognition and scaffold hopping was exploited to discover novel PTP1B inhibitors based on the known PTP1B inhibitor Ertiprotafib. A composite pharmacophore model was proposed from the interaction mode of Ertiprotafib, and 21 diverse molecules from five distinct structural classes were designed and synthesized accordingly. New compounds with considerable inhibition against PTP1B were identified from each series, and the most active compound 3a showed IC50 value of 1.3 μmol L(-1) against human recombinant PTP1B. Docking study indicated that the new inhibitors assumed binding modes similar to that of Ertiprotafib.
authors.affiliation: Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Jun-Zheng
authors.initials: JZ
authors.lastname: Liu
authors.forename: Shu-En
authors.initials: SE
authors.lastname: Zhang
authors.forename: Feilin
authors.initials: F
authors.lastname: Nie
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Tang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yin
authors.forename: Jin-Ying
authors.initials: JY
authors.lastname: Tian
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.forename: Zhiyan
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010666:Phenylpropionates; D013876:Thiophenes; C498182:ertiprotafib; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Ertiprotafib; PTP1B inhibitors; Pharmacophore; Scaffold hopping