排序方式: 共有22条查询结果,搜索用时 15 毫秒
1.
Colin H. MacKinnon Kevin Lau Jason D. Burch Yuan Chen Jonathon Dines Xiao Ding Charles Eigenbrot Alexander Heifetz Allan Jaochico Adam Johnson Joachim Kraemer Susanne Kruger Thomas M. Krülle Marya Liimatta Justin Ly Rosemary Maghames Christian A.G.N. Montalbetti Daniel F. Ortwine Zhonghua Pei 《Bioorganic & medicinal chemistry letters》2013,23(23):6331-6335
Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes. 相似文献
2.
Birong Zhang James R. Kiefer Robert A. Blake Jae H. Chang Steven Hartman Ellen Rei Ingalla Tracy Kleinheinz Vidhi Mody Michelle Nannini Daniel F. Ortwine Yingqing Ran Amy Sambrone Deepak Sampath Maia Vinogradova Yu Zhong Jerome C. Nwachukwu Kendall W. Nettles Tommy Lai Jun Liang 《Bioorganic & medicinal chemistry letters》2019,29(7):905-911
Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays. 相似文献
3.
A rationalization of the acidic pH dependence for stromelysin-1 (Matrix metalloproteinase-3) catalysis and inhibition 总被引:2,自引:0,他引:2
Johnson LL Pavlovsky AG Johnson AR Janowicz JA Man CF Ortwine DF Purchase CF White AD Hupe DJ 《The Journal of biological chemistry》2000,275(15):11026-11033
The pH dependence of matrix metalloproteinase (MMP) catalysis is described by a broad bell-shaped curve, indicating the involvement of two unspecified ionizable groups in proteolysis. Stromelysin-1 has a third pK(a) near 6, resulting in a uniquely sharp acidic catalytic optimum, which has recently been attributed to His(224). This suggests the presence of a critical, but unidentified, S1' substructure. Integrating biochemical characterizations of inhibitor-enzyme interactions with active site topography from corresponding crystal structures, we isolated contributions to the pH dependence of catalysis and inhibition of active site residues Glu(202) and His(224). The acidic pK(a) 5.6 is attributed to the Glu(202).zinc.H(2)O complex, consistent with a role for the invariant active site Glu as a general base in MMP catalysis. The His(224)-dependent substructure is identified as a tripeptide (Pro(221)-Leu(222)-Tyr(223)) that forms the substrate cleft lower wall. Substrate binding induces a beta-conformation in this sequence, which extends and anchors the larger beta-sheet of the enzyme. substrate complex and appears to be essential for productive substrate binding. Because the PXY tripeptide is strictly conserved among MMPs, this "beta-anchor" may represent a common motif required for macromolecular substrate hydrolysis. The striking acidic profile of stromelysin-1 defined by the combined ionization of Glu(202) and His(224) allows the design of highly selective inhibitors. 相似文献
4.
Johnson AR Pavlovsky AG Ortwine DF Prior F Man CF Bornemeier DA Banotai CA Mueller WT McConnell P Yan C Baragi V Lesch C Roark WH Wilson M Datta K Guzman R Han HK Dyer RD 《The Journal of biological chemistry》2007,282(38):27781-27791
Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients. 相似文献
5.
Warmus JS Quinn CL Taylor C Murphy ST Johnson TA Limberakis C Ortwine D Bronstein J Pagano P Knafels JD Lightle S Mochalkin I Brideau R Podoll T 《Bioorganic & medicinal chemistry letters》2012,22(7):2536-2543
Lipid A is an essential component of the Gram negative outer membrane, which protects the bacterium from attack of many antibiotics. The Lipid A biosynthesis pathway is essential for Gram negative bacterial growth and is unique to these bacteria. The first committed step in Lipid A biosynthesis is catalysis by LpxC, a zinc dependent deacetylase. We show the design of an LpxC inhibitor utilizing a robust model which directed efficient design of picomolar inhibitors. Analysis of physiochemical properties drove design to focus on an optimal lipophilicity profile. Further structure based design took advantage of a conserved water network over the active site, and with the optimal lipophilicity profile, led to an improved LpxC inhibitor with in vivo activity against wild type Pseudomonas aeruginosa. 相似文献
6.
Numerous transposed sequences of mitochondrial cytochrome oxidase I-II in aphids of the genus Sitobion (Hemiptera: Aphididae) 总被引:4,自引:1,他引:3
Polymerase chain reaction (PCR) products corresponding to 803 bp of the
cytochrome oxidase subunits I and II region of mitochondrial DNA (mtDNA
COI-II) were deduced to consist of multiple haplotypes in three Sitobion
species. We investigated the molecular basis of these observations. PCR
products were cloned, and six clones from one individual per species were
sequenced. In each individual, one sequence was found commonly, but also
two or three divergent sequences were seen. The divergent sequences were
shown to be nonmitochondrial by sequencing from purified mtDNA and Southern
blotting experiments. All seven nonmitochondrial clones sequenced to
completion were unique. Nonmitochondrial sequences have a high proportion
of unique sites, and very few characters are shared between
nonmitochondrial clones to the exclusion of mtDNA. From these data, we
infer that fragments of mtDNA have been transposed separately (probably
into aphid chromosomes), at a frequency only known to be equalled in
humans. The transposition phenomenon appears to occur infrequently or not
at all in closely related genera and other aphids investigated. Patterns of
nucleotide substitution in mtDNA inferred over a parsimony tree are very
different from those in transposed sequences. Compared with mtDNA,
nonmitochondrial sequences have less codon position bias, more even
exchanges between A, G, C and T, and a higher proportion of nonsynonymous
replacements. Although these data are consistent with the transposed
sequences being under less constraint than mtDNA, changes in the
nonmitochondrial sequences are not random: there remains significant
position bias, and probable excesses of synonymous replacements and of
conservative inferred amino acid replacements. We conclude that a
proportion of the inferred change in the nonmitochondrial sequences
occurred before transposition. We believe that Sitobion aphids (and other
species exhibiting mtDNA transposition) may be important for studying the
molecular evolution of mtDNA and pseudogenes. However, our data highlight
the need to establish the true evolutionary relationships between sequences
in comparative investigations.
相似文献
7.
8.
Natural bond orbital (NBO) studies of model compounds of glutathione peroxidase and its mimics are used to examine the relative strengths of nitrogen and oxygen donor groups in simple models and ω-substituted selenenic acids. Nitrogen-containing groups are generally better donors, but the weak Lewis basicity of the amide nitrogen allows for preferential interaction with the carbonyl oxygen which suggests that the glutamine of the GPX catalytic triad influences activity through an Se?O interaction. 相似文献
9.
Parker MH Ortwine DF O'Brien PM Lunney EA Banotai CA Mueller WT McConnell P Brouillette CG 《Bioorganic & medicinal chemistry letters》2000,10(21):2427-2430
Isothermal titration calorimetry was used to analyze the binding of an enantiomeric pair of inhibitors to the stromelysin-1 catalytic domain. Differences in binding affinity are attributable to different conformational entropy penalties suffered upon binding. Two possible explanations for these differences are proposed. 相似文献
10.
Jun Liang Sharada Labadie Birong Zhang Daniel F. Ortwine Snahel Patel Maia Vinogradova James R. Kiefer Till Mauer Victor S. Gehling Jean-Christophe Harmange Richard Cummings Tommy Lai Jiangpeng Liao Xiaoping Zheng Yichin Liu Amy Gustafson Erica Van der Porten Weifeng Mao Lesley Murray 《Bioorganic & medicinal chemistry letters》2017,27(13):2974-2981
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C–C bond between the pyrrolidine and pyridine. Replacing this with a C–N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (Log D) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5 mg/kg resulted in unbound Cmax ~2-fold of its cell potency (PC9 H3K4Me3 0.96 μM), meeting our criteria for an in vivo tool compound from a new scaffold. 相似文献