A5065950640- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Estrogen and related hormone effects
- Pharmacogenetics and Drug Metabolism
- Steroid Chemistry and Biochemistry
- Chemical Synthesis and Analysis
- Chemical Reactions and Isotopes
- Phosphodiesterase function and regulation
- Hormonal Regulation and Hypertension
- Hormonal and reproductive studies
- Cannabis and Cannabinoid Research
- Amino Acid Enzymes and Metabolism
- Alzheimer's disease research and treatments
- Protein Kinase Regulation and GTPase Signaling
- Cholinesterase and Neurodegenerative Diseases
- Ubiquitin and proteasome pathways
- Acute Lymphoblastic Leukemia research
- Metal-Catalyzed Oxygenation Mechanisms
- Chemical Reaction Mechanisms
- Metabolism and Genetic Disorders
- Inflammatory mediators and NSAID effects
- Enzyme Structure and Function
- Mass Spectrometry Techniques and Applications
- Cytomegalovirus and herpesvirus research
- Neuroscience and Neuropharmacology Research
Janssen (United States)
2019-2023
GlaxoSmithKline (United States)
2001-2022
Springhouse
2021
AstraZeneca (United States)
2002-2018
AstraZeneca (United Kingdom)
2007-2015
Research Triangle Park Foundation
1994-2006
Target (United States)
2004
Laboratory of Molecular Genetics
2001
University of California, Berkeley
1992-1998
GlaxoSmithKline (Netherlands)
1995-1998
Fragment-based lead generation has led to the discovery of a novel series cyclic amidine-based inhibitors β-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution these fragments using X-ray crystallography together determination surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around identification related...
Cerebral deposition of amyloid β-protein (Aβ) is believed to play a key role in the pathogenesis Alzheimer's disease. Because Aβ produced from processing precursor (APP) by β- and γ-secretases, these enzymes are considered important therapeutic targets for identification drugs treat Unlike β-secretase, which monomeric aspartyl protease, γ-secretase activity resides as part membrane-bound, high molecular weight, macromolecular complex. Pepstatin L685458 among several structural classes...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOxygen-18 kinetic isotope effects in the dopamine .beta.-monooxygenase reaction: Evidence for a new chemical mechanism non-heme, metallomonooxygenaseGaochao Tian, Joseph A. Berry, and Judith P. KlinmanCite this: Biochemistry 1994, 33, 1, 226–234Publication Date (Print):January 11, 1994Publication History Published online1 May 2002Published inissue 11 January...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnthalpic and entropic contributions to actin stability: calorimetry, circular dichroism, fluorescence study effects of calciumA. Bertazzon, G. H. Tian, A. Lamblin, Tian Yow TsongCite this: Biochemistry 1990, 29, 1, 291–298Publication Date (Print):January 9, 1990Publication History Published online1 May 2002Published inissue 9 January 1990https://pubs.acs.org/doi/10.1021/bi00453a040https://doi.org/10.1021/bi00453a040research-articleACS...
Transition state analogs pepstatin methylester (PME) and L685458 have been shown to inhibit γ-secretase non-competitively (Tian, G., Sobotka-Briner, C., Zysk, J., Liu, X., Birr, Sylvester, M. A., Edwards, P. D., Scott, C. W., Greenberg, B. D. (2002) J. Biol. Chem. 277, 31499–31505). This unusual kinetics suggests physical separation of the sites for substrate binding catalysis with transition catalytic site not site. Methods inhibitor cross-competition competition ligand were utilized...
Tyrosine hydroxylase converts tyrosine to dihydroxyphenylalanine utilizing a tetrahydropterin cofactor and molecular oxygen. Previous deuterium isotope effect studies have raised the possibility that activation of oxygen might be rate-limiting step for this reaction. To test validity proposal, we measured 18O kinetic effects reaction as function amino acid substrate, derivative, pH. The are nearly constant in every condition tested with an average value 1.0175 ± 0.0019. These results...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanism of Time-Dependent Inhibition 5.alpha.-Reductases by .DELTA.1-4-Azasteroids: Toward Perfection Rates Using Ligand-Binding EnergiesGaochao Tian, Robert Mook, Marcia L. Moss, and Stephen V. FryeCite this: Biochemistry 1995, 34, 41, 13453–13459Publication Date (Print):October 17, 1995Publication History Published online1 May 2002Published inissue 17 October...
The interactions between (R)-rolipram and purified human recombinant low-Km, cAMP-specific phosphodiesterase (HSPDE4B2B) constructs were investigated using biochemical, kinetic, biophysical approaches. full-length protein (amino acids 1-564) an N-terminal truncated 81-564) exhibited high-affinity binding, whereas C-terminal 152-528) lacked binding. 152-528 81-564 proteins had similar Km's kcat/Km's differed less than 4-fold compared with the 1-564 protein. (R)-Rolipram inhibition plots...
The salt-inducible kinases (SIK) 1–3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. lack highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study optimal isoform selectivity profile suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy developing potent that selective against other by engaging two differentiating features catalytic...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDiscrimination between 16O and 18O in oxygen binding to the reversible carriers hemoglobin, myoglobin, hemerythrin, hemocyanin: a new probe for reductive activation by proteinsGaochao Tian Judith P. KlinmanCite this: J. Am. Chem. Soc. 1993, 115, 20, 8891–8897Publication Date (Print):October 1, 1993Publication History Published online1 May 2002Published inissue 1 October...
Maturation of gamma-secretase requires an endoproteolytic cleavage in presenilin-1 (PS1) within a peptide loop encoded by exon 9 the corresponding gene. Deletion has been demonstrated to cause familial Alzheimer's disease. A synthetic sequence was found inhibit cell-free enzymatic assay with IC(50) 2.1 microM, value similar K(m) (3.5 microM) for substrate C100. Truncation at either end, single amino acid substitutions certain residues, reversal, or randomization reduced its potency. Similar...
Selective cyclooxygenase (COX)-2 inhibitors have been extensively studied for colorectal cancer (CRC) chemoprevention. Celecoxib has reported to reduce the incidence of adenomas and CRC but is also associated with an increased risk cardiovascular events. Here, we report a series gut-restricted, selective COX-2 characterized by high colonic exposure minimized systemic exposure. By establishing acute ex vivo 18F-FDG uptake attenuation as efficacy proxy, identified subset analogues that...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT17.beta.-(N-tert-Butylcarbamoyl)-4-aza-5.alpha.-androstan-1-en-3-one Is an Active Site-Directed Slow Time-Dependent Inhibitor of Human Steroid 5.alpha.-Reductase 1Gaochao Tian, J. Darren Stuart, Marcia L. Moss, Paul Domanico, H. Neal Bramson, Indravadan R. Patel, Sue Kadwell, Laurie K. Overton, Thomas A. Kost, and Cite this: Biochemistry 1994, 33, 8, 2291–2296Publication Date (Print):March 1, 1994Publication History Published online1 May...
The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for degradation of endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition 2-AG leads to elevation 2-AG, most abundant endogenous agonist cannabinoid receptors (CBs) CB1 CB2. Activation these has demonstrated beneficial effects on mood, appetite, pain, inflammation. Therefore, MAGL inhibitors have potential produce therapeutic in a vast array complex human...
Abstract 8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The from reaction, 8-oxoguanine, and its analogues, 8-bromoguanine 8-aminoguanine, trigger rate-limiting AP precise activation mechanism remains unclear. product-assisted catalysis hypothesis suggests that 8-oxoguanine...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure-Activity Relationships for Inhibition of Type 1 and 2 Human 5.alpha.-Reductase Adrenal 3.beta.-Hydroxy-.DELTA.5-steroid Dehydrogenase/3-Keto-.DELTA.5-steroid Isomerase by 6-Azaandrost-4-en-3-ones: Optimization the C17 SubstituentStephen V. Frye, Curt D. Haffner, Patrick R. Maloney, Roger N. Hiner, George F. Dorsey, Robert A. Noe, Rayomand J. Unwalla, Kenneth W. Batchelor, H. Neal Bramson, Darren Stuart, Stephanie L. Schweiker, John Van...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTOxygen isotope effect on activated bleomycin stabilityRichard M. Burger, Gaochao Tian, and Karl DrlicaCite this: J. Am. Chem. Soc. 1995, 117, 3, 1167–1168Publication Date (Print):January 1, 1995Publication History Published online1 May 2002Published inissue 1 January 1995https://pubs.acs.org/doi/10.1021/ja00108a049https://doi.org/10.1021/ja00108a049research-articleACS PublicationsRequest reuse permissionsArticle Views111Altmetric-Citations41LEARN...
The kinetic mechanisms for the inhibition of pp60c-src tyrosine kinase (Src TK) by 4-anilinoquinazolines, an important class chemicals as protein inhibitors, were investigated. 4-Anilinoquinazolines with a bulky group at 4'-position anilino shown to be competitive both ATP and peptide, whereas molecules lacking such only displayed pattern typical those noncompetitive peptide. Modifications substituents on carbocyclic ring did not perturb although affinities these modified inhibitors Src TK...
We have discovered that 17beta-[N,N-(diethyl)carbamoyl]-6-azaandrost-4-en-3-one is a time-dependent inhibitor of type II 5alpha-reductase, as the drug finasteride. Unlike finasteride, 6-aza-steroid not I 5 alpha-reductase. Finasteride inhibition enzyme proceeds in two-step mechanism. At pH 6 and 37 degrees C, an initial finasteride-reductase complex formed with K(i)(app) 11.9 +/- 4.1 nM. In second step, irreversible rate constant inactivation 0.09 0.01 s(-1). contrast, reversible inhibitor....
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMechanism of adenylate kinase. Histidine-36 is not directly involved in catalysis, but protects cysteine-25 and stabilizes the tertiary structureGaochao Tian, Charles R. Sanders, II, Fumio Kishi, Atsushi Nakazawa, Ming Daw TsaiCite this: Biochemistry 1988, 27, 15, 5544–5552Publication Date (Print):July 1, 1988Publication History Published online1 May 2002Published inissue 1 July...
Abstract Despite glutathione’s long-recognized role as a major cellular antioxidant and its central in ferroptosis defense, inhibition of glutathione biosynthetic enzymes has received little attention target for the therapeutic induction ferroptosis. Here, we report that small-molecule glutamate–cysteine ligase (GCL), rate-limiting enzyme biosynthesis, selectively potently kills cancer cells by We further describe novel GCL inhibitors including KOJ-1 KOJ-2, compounds with excellent potency...
Fatty acid amide hydrolase (FAAH) has emerged as a potential target for developing analgesic, anxiolytic, antidepressant, sleep-enhancing, and anti-inflammatory drugs, tremendous efforts have been made to discover potent selective inhibitors of FAAH. Most known FAAH described date employ covalent mechanisms, inhibiting the enzyme either reversibly or irreversibly. Recently, benzothiazole-based analogue (1) possessing high potency against yet lacking structural feature previously interact...