title: Synthesis, bioactivity, docking and molecular dynamics studies of furan-based peptides as 20S proteasome inhibitors.
abstract: Proteasome inhibitors are promising compounds for a number of therapies, including cardiovascular and eye diseases, diabetes, and cancers. We previously reported a series of furan-based peptidic inhibitors with moderate potencies against the proteasome β5 subunit, hypothesizing that the C-terminal furyl ketone motif could form a covalent bond with the catalytic residue, threonine 1. In this context, we describe further optimizations of the furan-based peptides, and a series of dipeptidic and tripeptidic inhibitors were designed and synthesized, aiming at improved potency and better solubility. Most of the tripeptidic inhibitors demonstrated improved potency and selectivity as β5 subunit inhibitors in both enzymatic and cellular assays, and good antineoplastic activities in various tumor cell lines were also observed. However, no inhibitory effects were observed for the dipeptidic compounds, which led us to presume that a noncovalent binding mode is adopted. Docking studies and molecular dynamics simulations were carried out to verify this presumption, with results showing that the distance between the furyl ketone motif and Thr1 is slightly too long to form covalent bond.
authors: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191 (China).
authors: Qi
authors: Q
authors: Sun
authors: Bo
authors: B
authors: Xu
authors: Yan
authors: Y
authors: Niu
authors: Fengrong
authors: F
authors: Xu
authors: Lei
authors: L
authors: Liang
authors: Chao
authors: C
authors: Wang
authors: Jiapei
authors: J
authors: Yu
authors: Gang
authors: G
authors: Yan
authors: Wei
authors: W
authors: Wang
authors: Hongwei
authors: H
authors: Jin
authors: Ping
authors: P
authors: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D057786:Peptidomimetics; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C039281:furan
keywords: antitumor agents; docking; dynamic simulations; furans; peptides; proteasome inhibitors