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1.
PLoS One ; 17(10): e0275027, 2022.
Article in English | MEDLINE | ID: mdl-36197897

ABSTRACT

Many mental health disorders are characterized by an impaired ability, or willingness, to exert effort to obtain rewards. This impairment is modeled in effort-based decision tasks, and neuropharmacological studies implicate dopamine in this process. However, other transmitter systems such as opioidergic and cholinergic systems have received less attention. Here, in two separate studies we tested the acute effects of naltrexone and nicotine on effort-based decision-making in healthy adults. In Study 1, we compared naltrexone (50mg and 25mg) to placebo, and in Study 2, a pilot study, we compared nicotine (7mg) to placebo. In both studies, participants completed the Effort Expenditure for Rewards Task (EEfRT), which measured effort-based decision-making related to monetary rewards. Although subjects expended greater effort for larger reward magnitude and when there was a higher probability of receiving the reward, neither naltrexone nor nicotine affected willingness to exert effort for monetary rewards. Although the drugs produced significant and typical drug effects on measures of mood and behavior, they did not alter effort-based decision-making. This has implications both for the clinical use of these drugs, as well as for understanding the neuropharmacology of effort-related behavior.


Subject(s)
Naltrexone , Nicotine , Adult , Cholinergic Agents/pharmacology , Decision Making , Dopamine/pharmacology , Humans , Motivation , Naltrexone/pharmacology , Nicotine/pharmacology , Pilot Projects , Reward
2.
Ecology ; 103(2): e03573, 2022 02.
Article in English | MEDLINE | ID: mdl-34710235

ABSTRACT

Optimal design procedures provide a framework to leverage the learning generated by ecological models to flexibly and efficiently deploy future monitoring efforts. At the same time, Bayesian hierarchical models have become widespread in ecology and offer a rich set of tools for ecological learning and inference. However, coupling these methods with an optimal design framework can become computationally intractable. Recursive Bayesian computation offers a way to substantially reduce this computational burden, making optimal design accessible for modern Bayesian ecological models. We demonstrate the application of so-called prior-proposal recursive Bayes to optimal design using a simulated data binary regression and the real-world example of monitoring and modeling sea otters in Glacier Bay, Alaska. These examples highlight the computational gains offered by recursive Bayesian methods and the tighter fusion of monitoring and science that those computational gains enable.


Subject(s)
Otters , Research Design , Alaska , Animals , Bayes Theorem , Models, Theoretical
3.
Front Vet Sci ; 8: 639335, 2021.
Article in English | MEDLINE | ID: mdl-33996969

ABSTRACT

Dietary fiber affects canine physiology in many ways, such as increasing colonic absorption of water and improving gut health, both of which may positively impact exercise performance. The objectives of this study were to investigate the effects of increased dietary soluble fiber and incremental training on respiratory rate (RR), internal body temperature (BT), body composition, and fecal metabolites in mid-distance training sled dogs. Fourteen dogs (12 Siberian and 2 Alaskan Huskies) were blocked by age, sex, and body weight (BW) and then randomly allocated into one of two diet groups. Seven dogs were fed a dry extruded control diet (Ctl) with an insoluble:soluble fiber ratio of 4:1 (0.74% soluble fiber on a dry-matter basis), and seven dogs were fed a dry extruded treatment diet (Trt) with an insoluble:soluble fiber ratio of 3:1 (2.12% soluble fiber on a dry-matter basis). Fecal samples were taken once a week. All dogs underwent 9 weeks of incremental exercise conditioning where the running distance was designed to increase each week. Every 3 weeks, external telemetry equipment was used to non-invasively measure and record RR and internal BT at resting, working, and post-exercise recovery states. Body composition was measured on weeks -1 and 9 using quantitative magnetic resonance. Body composition, RR, BT, and fecal metabolites were analyzed using a mixed model with dog as a random effect and week and diet group as fixed effects. Dogs on Trt had lower working and post-exercise BT than Ctl (P < 0.05). In addition, Trt dogs had lower recovery BT at weeks 2 and 5 than Ctl dogs (P < 0.05). Treatment dogs had greater fecal short-chain fatty acid concentrations than Ctl (P < 0.05). Diet had no effect on RR or body composition (P > 0.10), but exercise resulted in an overall 7% increase in lean and 3.5% decrease in fat mass (P < 0.05). These data suggest that increasing dietary soluble fiber may positively influence BT and gut health; however, it has no effect on RR or body composition. Soluble fiber did not negatively impact any measures of overall health and performance and should be considered for use in performance dogs.

4.
Vet Sci ; 7(3)2020 Jul 23.
Article in English | MEDLINE | ID: mdl-32717797

ABSTRACT

Tryptophan (Trp), an indispensable amino acid for dogs, is the precursor of serotonin, a neurotransmitter with a variety of effects throughout the body, including the ability to modulate cardiac and pulmonary activity. This study aimed to investigate the effects of a 12-week incremental exercise regimen and supplemental dietary Trp on heart rate (HR) and respiratory rate (RR) in client-owned sled dogs. Sixteen Siberian huskies were randomly allocated to either treatment or control diet groups. Both groups were fed a control diet (Trp to large neutral amino acid ratio of 0.047:1); however, treatment dogs received a Trp supplement to achieve a Trp to large neutral amino acid ratio of 0.075:1. Every three weeks, external telemetry equipment was used to non-invasively measure and record HR and RR at a resting, working, and post-exercise state in a controlled exercise challenge. A mixed model was used to test differences between diet, activity parameter, and week. Dietary Trp supplementation had no effect on HR or RR. Independent of diet, resting, working, post-exercise HR, and time to recover post-exercise HR decreased from week -1 to week 11 (p < 0.05). Resting HR had the greatest reduction from week -1 to week 11 (21%, p < 0.05). Working RR did not change with exercise (p > 0.10), but rRR and postRR decreased from week -1 to week 11 (p < 0.05). These data suggest that the exercise regimen the dogs were subjected to may have positively impacted the dogs' capacity to sustain aerobic exercise, whereas Trp supplementation had no effect on HR or RR.

5.
J Chem Inf Model ; 60(4): 2091-2099, 2020 04 27.
Article in English | MEDLINE | ID: mdl-32131596

ABSTRACT

Induction of cytochrome P450 isoform 3A4 via activation of the pregnane xenobiotic receptor (PXR) is a concern for pharmaceutical discovery and development, as it can lead to drug-drug interactions. We present a novel molecular descriptor, the smallest maximum intramolecular distance (SMID), which is correlated with PXR activation, and a method for using the SMID descriptor to guide discovery chemists in modifying lead compounds to decrease PXR activation.


Subject(s)
Receptors, Steroid , Cytochrome P-450 CYP3A , Drug Interactions , Pregnane X Receptor , Pregnanes , Xenobiotics/toxicity
6.
Ecology ; 99(3): 524-535, 2018 03.
Article in English | MEDLINE | ID: mdl-29369341

ABSTRACT

Population dynamics vary in space and time. Survey designs that ignore these dynamics may be inefficient and fail to capture essential spatio-temporal variability of a process. Alternatively, dynamic survey designs explicitly incorporate knowledge of ecological processes, the associated uncertainty in those processes, and can be optimized with respect to monitoring objectives. We describe a cohesive framework for monitoring a spreading population that explicitly links animal movement models with survey design and monitoring objectives. We apply the framework to develop an optimal survey design for sea otters in Glacier Bay. Sea otters were first detected in Glacier Bay in 1988 and have since increased in both abundance and distribution; abundance estimates increased from 5 otters to >5,000 otters, and they have spread faster than 2.7 km/yr. By explicitly linking animal movement models and survey design, we are able to reduce uncertainty associated with forecasting occupancy, abundance, and distribution compared to other potential random designs. The framework we describe is general, and we outline steps to applying it to novel systems and taxa.


Subject(s)
Ecology , Otters , Animals , Population Dynamics
7.
ACS Med Chem Lett ; 8(5): 486-491, 2017 May 11.
Article in English | MEDLINE | ID: mdl-28523098

ABSTRACT

A data-centric medicinal chemistry approach led to the invention of a potent and selective IDO1 inhibitor 4f, INCB24360 (epacadostat). The molecular structure of INCB24360 contains several previously unknown or underutilized functional groups in drug substances, including a hydroxyamidine, furazan, bromide, and sulfamide. These moieties taken together in a single structure afford a compound that falls outside of "drug-like" space. Nevertheless, the in vitro ADME data is consistent with the good cell permeability and oral bioavailability observed in all species (rat, dog, monkey) tested. The extensive intramolecular hydrogen bonding observed in the small molecule crystal structure of 4f is believed to significantly contribute to the observed permeability and PK. Epacadostat in combination with anti-PD1 mAb pembrolizumab is currently being studied in a phase 3 clinical trial in patients with unresectable or metastatic melanoma.

8.
Ecology ; 98(2): 328-336, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28052322

ABSTRACT

Ecological invasions and colonizations occur dynamically through space and time. Estimating the distribution and abundance of colonizing species is critical for efficient management or conservation. We describe a statistical framework for simultaneously estimating spatiotemporal occupancy and abundance dynamics of a colonizing species. Our method accounts for several issues that are common when modeling spatiotemporal ecological data including multiple levels of detection probability, multiple data sources, and computational limitations that occur when making fine-scale inference over a large spatiotemporal domain. We apply the model to estimate the colonization dynamics of sea otters (Enhydra lutris) in Glacier Bay, in southeastern Alaska.


Subject(s)
Models, Theoretical , Otters/physiology , Animals , Ecology , Ecosystem , Population Dynamics
9.
Environ Monit Assess ; 185(1): 405-14, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22350349

ABSTRACT

We used variance components to assess allocation of sampling effort in a hierarchically nested sampling design for ongoing monitoring of early life history stages of the federally endangered Devils Hole pupfish (DHP) (Cyprinodon diabolis). Sampling design for larval DHP included surveys (5 days each spring 2007-2009), events, and plots. Each survey was comprised of three counting events, where DHP larvae on nine plots were counted plot by plot. Statistical analysis of larval abundance included three components: (1) evaluation of power from various sample size combinations, (2) comparison of power in fixed and random plot designs, and (3) assessment of yearly differences in the power of the survey. Results indicated that increasing the sample size at the lowest level of sampling represented the most realistic option to increase the survey's power, fixed plot designs had greater power than random plot designs, and the power of the larval survey varied by year. This study provides an example of how monitoring efforts may benefit from coupling variance components estimation with power analysis to assess sampling design.


Subject(s)
Environmental Monitoring/methods , Killifishes , Statistics as Topic , Analysis of Variance , Animals , Endangered Species , Nevada
10.
J Med Chem ; 52(23): 7364-7, 2009 Dec 10.
Article in English | MEDLINE | ID: mdl-19507862

ABSTRACT

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC(50) = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.


Subject(s)
Binding, Competitive , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Melanoma/enzymology , Amidines/chemistry , Amidines/metabolism , Amidines/pharmacology , Amidines/therapeutic use , Animals , Disease Models, Animal , Disease Progression , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry , Inhibitory Concentration 50 , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mice , Models, Molecular , Molecular Conformation
11.
Proc Natl Acad Sci U S A ; 105(31): 10837-42, 2008 Aug 05.
Article in English | MEDLINE | ID: mdl-18658235

ABSTRACT

The genetic impacts of hybridization between native and introduced species are of considerable conservation concern, while the possibility of reticulate evolution affects our basic understanding of how species arise and shapes how we use genetic data to understand evolutionary diversification. By using mitochondrial NADH dehydrogenase subunit 2 (ND2) sequences and 467 amplified fragment-length polymorphism nuclear DNA markers, we show that the introduced white sucker (Catostomus commersoni) has hybridized with two species native to the Colorado River Basin--the flannelmouth sucker (Catostomus latipinnis) and the bluehead sucker (Catostomus discobolus). Hybrids between the flannelmouth sucker and white sucker have facilitated introgression between the two native species, previously isolated by reproductive barriers, such that individuals exist with contributions from all three genomes. Most hybrids had the mitochondrial haplotype of the introduced white sucker, emphasizing its pivotal role in this three-way hybridization. Our findings highlight how introduced species can threaten the genetic integrity of not only one species but also multiple previously reproductively isolated species. Furthermore, this complex three-way reticulate (as opposed to strictly bifurcating) evolution suggests that seeking examples in other vertebrate systems might be productive. Although the present study involved an introduced species, similar patterns of hybridization could result from natural processes, including stream capture or geological formations (e.g., the Bering land bridge).


Subject(s)
Cypriniformes/genetics , Genetics, Population , Hybridization, Genetic , Phylogeny , Amplified Fragment Length Polymorphism Analysis , Animals , Base Sequence , Bayes Theorem , DNA Primers/genetics , Molecular Sequence Data , Population Dynamics , Sequence Analysis, DNA , Wyoming
12.
Bioorg Med Chem Lett ; 18(1): 66-71, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18037290

ABSTRACT

The structure-based design and synthesis of isothiazolidinone (IZD) inhibitors of PTP1B containing imidazoles and imidazolines and their modification to interact with the B site of PTP1B are described here. The X-ray crystal structures of 3I and 4I complexed with PTP1B were solved and revealed the inhibitors are interacting extensively with the B site of the enzyme.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Crystallography, X-Ray , Drug Design , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Imidazolines/chemical synthesis , Imidazolines/chemistry , Imidazolines/pharmacology , Models, Molecular , Structure-Activity Relationship , Thiazoles/chemical synthesis
13.
J Med Chem ; 50(4): 603-6, 2007 Feb 22.
Article in English | MEDLINE | ID: mdl-17256836

ABSTRACT

The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.


Subject(s)
Amides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Hydroxamic Acids/chemical synthesis , Piperidines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Administration, Oral , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Drug Synergism , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Mice , Molecular Conformation , Piperidines/chemistry , Piperidines/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Stereoisomerism , Structure-Activity Relationship , Transplantation, Heterologous , Trastuzumab
14.
Dis Aquat Organ ; 78(2): 129-36, 2007 Dec 13.
Article in English | MEDLINE | ID: mdl-18286809

ABSTRACT

Black spot is a common disease syndrome of freshwater fishes. This study provides information on the rank of density of the black spot agent and opercular bone alterations associated with at least one digenean, Uvulifer sp., infecting native and non-native catostomids and cyprinids of the Upper Colorado River Basin. We evaluated the density rank of pigmented metacercariae and associated alterations in the operculum of the bluehead sucker Catostomus discobolus, flannelmouth sucker C. latipinnis, white sucker C. commersoni, catostomid hybrids, roundtail chub Gila robusta, and creek chub Semotilus atromaculatus, sampled from Muddy Creek, Wyoming, USA in 2003 or 2004. All fish species contained individuals that exhibited gross signs of the black spot agent. Bluehead and flannelmouth suckers had 100% prevalence of infection. Although the other suckers and chubs contained encysted metacercariae in at least one individual, the presence of pigmented metacercariae was not apparent (i.e. based on gross observations) in many individuals. Catostomids had higher densities of metacercariae than cyprinids, as shown by frequency distributions of density ranks. Opercular holes (i.e. holes that completely penetrated the opercle and were in direct association with the pigment associated metacercariae) and pockets (depressions on the external surface of the opercle associated with metacercariae) were abundant among catostomids but rare among cyprinids.


Subject(s)
Cyprinidae/parasitology , Cypriniformes/parasitology , Fish Diseases/parasitology , Trematoda/pathogenicity , Trematode Infections/veterinary , Animals , Desert Climate , Fish Diseases/pathology , Population Density , Trematoda/isolation & purification , Trematode Infections/parasitology , Trematode Infections/pathology , Wyoming
15.
J Biol Chem ; 281(43): 32784-95, 2006 Oct 27.
Article in English | MEDLINE | ID: mdl-16916797

ABSTRACT

Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.


Subject(s)
Molecular Mimicry , Organophosphonates/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Thiazoles/pharmacology , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Escherichia coli/genetics , Humans , Hydrogen Bonding , Hydrolysis , Inhibitory Concentration 50 , Kinetics , Models, Molecular , Molecular Structure , Protein Conformation/drug effects , Protein Structure, Secondary , Protein Structure, Tertiary , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/analysis , Protein Tyrosine Phosphatases/isolation & purification , Structure-Activity Relationship , Substrate Specificity , Water/chemistry
16.
J Med Chem ; 49(13): 3774-89, 2006 Jun 29.
Article in English | MEDLINE | ID: mdl-16789735

ABSTRACT

Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.


Subject(s)
Benzimidazoles/chemical synthesis , Oligopeptides/chemistry , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Cell Line , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Mimicry , Molecular Structure , Phosphorylation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Insulin/metabolism , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology
17.
Bioorg Med Chem ; 14(17): 5833-49, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16769216

ABSTRACT

The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure-activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation.


Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Peptides/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Thiazoles/chemistry , Thiazoles/pharmacology , Escherichia coli , Humans , Models, Molecular , Molecular Structure , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Structure-Activity Relationship
18.
J Med Chem ; 48(21): 6544-8, 2005 Oct 20.
Article in English | MEDLINE | ID: mdl-16220970

ABSTRACT

Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.


Subject(s)
Dipeptides/chemical synthesis , Phosphotyrosine/chemistry , Protein Tyrosine Phosphatases/antagonists & inhibitors , Protein Tyrosine Phosphatases/chemistry , Thiazoles/chemical synthesis , Crystallography, X-Ray , Dipeptides/chemistry , Drug Design , Models, Molecular , Molecular Mimicry , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Quantitative Structure-Activity Relationship , Stereoisomerism , Thiazoles/chemistry
19.
Bioorg Med Chem Lett ; 13(6): 1191-4, 2003 Mar 24.
Article in English | MEDLINE | ID: mdl-12643941

ABSTRACT

The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38alpha kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38alpha kinase, which was predicted to have several key interactions in common with SB-203580, was confirmed by X-ray crystallography of 19 (p38 IC(50)=82 nM).


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Urea/chemical synthesis , Urea/pharmacology , Crystallography, X-Ray , Drug Design , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Structure-Activity Relationship , Urea/analogs & derivatives , p38 Mitogen-Activated Protein Kinases
20.
J Biol Chem ; 277(48): 46609-15, 2002 Nov 29.
Article in English | MEDLINE | ID: mdl-12244092

ABSTRACT

Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01.


Subject(s)
Alkaloids/pharmacology , Protein Kinase Inhibitors , Alkaloids/chemistry , Amino Acid Sequence , Checkpoint Kinase 1 , Models, Molecular , Molecular Sequence Data , Protein Conformation , Protein Kinases/chemistry , Staurosporine/analogs & derivatives , Structure-Activity Relationship
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