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Journal of Chemical Information and Modeling 11/2010; · 4.68 Impact Factor
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ABSTRACT: Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.
Combinatorial chemistry & high throughput screening 05/2010; 13(4):337-51. · 2.46 Impact Factor
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ABSTRACT: Recently, we identified a novel class of potent cathepsin L inhibitors, characterized by a thiocarbazate warhead. Given the potential of these compounds to inhibit other cysteine proteases, we designed and synthesized a library of thiocarbazates containing diversity elements at three positions. Biological characterization of this library for activity against a panel of proteases indicated a significant preference for members of the papain family of cysteine proteases over serine, metallo-, and certain classes of cysteine proteases, such as caspases. Several potent inhibitors of cathepsin L and S were identified. The SAR data were employed in docking studies in an effort to understand the structural elements required for cathepsin S inhibition. This study provides the basis for the design of highly potent and selective inhibitors of the papain family of cysteine proteases.
Combinatorial Chemistry & High Throughput Screening 04/2010; 13(4):337-351. · 1.78 Impact Factor
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Parag P Shah,
Michael C Myers, Mary Pat Beavers,
Jeremy E Purvis,
Huiyan Jing,
Heather J Grieser,
Elizabeth R Sharlow,
Andrew D Napper,
Donna M Huryn,
Barry S Cooperman,
Amos B Smith,
Scott L Diamond
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ABSTRACT: A novel small molecule thiocarbazate (PubChem SID 26681509), a potent inhibitor of human cathepsin L (EC 3.4.22.15) with an IC(50) of 56 nM, was developed after a 57,821-compound screen of the National Institutes of Health Molecular Libraries Small Molecule Repository. After a 4-h preincubation with cathepsin L, this compound became even more potent, demonstrating an IC(50) of 1.0 nM. The thiocarbazate was determined to be a slow-binding and slowly reversible competitive inhibitor. Through a transient kinetic analysis for single-step reversibility, inhibition rate constants were k(on) = 24,000 M(-1)s(-1) and k(off) = 2.2 x 10(-5) s(-1) (K(i) = 0.89 nM). Molecular docking studies were undertaken using the experimentally derived X-ray crystal structure of papain/CLIK-148 (1cvz. pdb). These studies revealed critical hydrogen bonding patterns of the thiocarbazate with key active site residues in papain. The thiocarbazate displayed 7- to 151-fold greater selectivity toward cathepsin L than papain and cathepsins B, K, V, and S with no activity against cathepsin G. The inhibitor demonstrated a lack of toxicity in human aortic endothelial cells and zebrafish. In addition, the thiocarbazate inhibited in vitro propagation of malaria parasite Plasmodium falciparum with an IC(50) of 15.4 microM and inhibited Leishmania major with an IC(50) of 12.5 microM.
Molecular pharmacology 08/2008; 74(1):34-41. · 4.53 Impact Factor
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ABSTRACT: Recently, we identified a thiocarbazate that exhibits potent inhibitory activity against human cathepsin L. Since this structure represents a novel chemotype with potential for activity against the entire cysteine protease family, we designed, synthesized, and assayed a series of analogs to probe the mechanism of action, as well as the structural requirements for cathepsin L activity. Molecular docking studies using coordinates of a papain-inhibitor complex as a model for cathepsin L provided useful insights.
Bioorganic & medicinal chemistry letters 07/2008; 18(12):3646-51. · 2.65 Impact Factor
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ABSTRACT: The first total synthesis of roquefortine C is achieved by implementation of a novel elimination strategy to construct the thermodynamically unstable E-dehydrohistidine moiety. Molecular modeling studies are presented which explain the instability of the roquefortine C structure compared to that of isoroquefortine C.
Journal of the American Chemical Society 06/2008; 130(19):6281-7. · 9.91 Impact Factor
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ABSTRACT: Substituted pyrazole esters were identified as hits in a high throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR) to identify inhibitors of the enzyme cathepsin B. Members of this class, along with functional group analogs, were synthesized in an effort to define the structural requirements for activity. Analog characterization was hampered by the need to include a reducing agent such as dithiothreitol (DTT) or cysteine in the assay, highlighting the caution required in interpreting biological data gathered in the presence of such nucleophiles. Despite the confounding effects of DTT and cysteine, our studies demonstrate that the pyrazole 1 acts as alternate substrate for cathepsin B, rather than as an inhibitor.
Bioorganic & Medicinal Chemistry Letters 10/2007; 17(17):4761-6. · 2.55 Impact Factor
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ABSTRACT: Metastin, also known as KiSS-1, the cognate ligand for the metastin receptor GPR54, is a peptide known to dramatically reduce metastasis in experimental models. Despite this, there is no reported structure for metastin nor any small molecule modulators of metastin function that could be used either clinically or experimentally. Here we report the NMR solution structure of a 13-residue metastin peptide in a membrane-like environment (SDS micelles) and find it to have a relatively stable helix conformation from residues 7 to 13. In assays for metastin receptor binding and calcium flux with receptor-transfected HEK-293 cells, we demonstrate through alanine scanning and amino acid substitutions that the peptide C-terminus shows helix periodicity in an NMR structural model and that Phe9, Arg12, and Phe13 are crucial to the activity of the peptide. These three residues lie on one face of the helix and define a pharmacophore site for metastin. We used these pharmacophore features in small molecule database searches to identify hits with submicromolar affinity for the metastin receptor. We also show here that molecules mimicking key elements of this pharmacophore site bind to the metastin receptor and act as full agonists, albeit with reduced potency compared to that of metastin itself. Together this structure-activity approach may yield pharmacologically useful compounds relevant in defining and modulating metastin receptor function.
Journal of Medicinal Chemistry 03/2007; 50(3):462-71. · 5.25 Impact Factor
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ABSTRACT: A series of indole-O-glucosides and C-glucosides was synthesized and evaluated in SGLT1 and SGLT2 cell-based functional assays. Compounds 2a and 2o were identified as potent SGLT2 inhibitors and screened in ZDF rats.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(6):1696-701. · 2.55 Impact Factor
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ABSTRACT: A series of benzo-fused heteroaryl-O-glucosides was synthesized and evaluated in SGLT1 and 2 cell-based functional assays. Indole-O-glucoside 10a and benzimidazole-O-glucoside 18 exhibited potent in vitro SGLT2 inhibitory activity.
Bioorganic & Medicinal Chemistry Letters 01/2006; 15(23):5202-6. · 2.55 Impact Factor
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ABSTRACT: A series of 3-anilino-quinoxalinones has been identified as a new class of glycogen phosphorylase inhibitors. The lead compound 1 was identified through high throughput screening as well as through pharmacophore-based electronic screening. Modifications were made to the scaffold of 1 to produce novel analogues, some of which are 25 times more potent than the lead compound.
Bioorganic & Medicinal Chemistry Letters 12/2005; 15(21):4790-3. · 2.55 Impact Factor
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ABSTRACT: Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4-17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities.
Journal of Biological Chemistry 04/2005; 280(9):8134-42. · 4.77 Impact Factor
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ABSTRACT: The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. Lead optimization afforded potent (IC(50) < 50 nM) and selective inhibitors of CatS demonstrating cellular activity and reversibility of enzyme inhibition.
Journal of Medicinal Chemistry 09/2004; 47(20):4799-801. · 5.25 Impact Factor
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Lan Shen,
Catherine Prouty,
Bruce R Conway,
Lori Westover,
Jun Z Xu,
Richard A Look,
Xin Chen, Mary Pat Beavers,
Jerry Roberts,
William V Murray,
Keith T Demarest,
Gee-Hong Kuo
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ABSTRACT: Palladium catalyzed cross-coupling reactions were used to synthesize two key intermediates 3 and 5 that resulted in the synthesis of novel series of macrocyclic bis-7-azaindolylmaleimides. Among the three series of macrocycles, the oxygen atom and thiophene containing linkers yielded molecules with higher inhibitory potency at GSK-3 beta (K(i)=0.011-0.079 microM) while the nitrogen atom containing linkers yielded molecules with lower potency (K(i)=0.150->1 microM). Compound 33 and 36 displayed 1-2 orders of magnitude selectivity at GSK-3 beta against CDK2, PKC beta II, Rsk3 and little or no inhibitions to the other 62 protein kinases. Compound 46 was at least 100-fold more selective towards GSK-3 beta than PKC beta II, and it had little or no activity against a panel of 65 protein kinases, almost behaved as a GSK-3 beta 'specific inhibitor'. All three compounds showed good potency in GS assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3 beta selectivity of azaindolylmaleimides. The high selectivity, inhibitory potency and cellular activities of these non-crown-ether typed molecules may provide them as a valuable pharmacological tools in elucidating the complex roles of GSK-3 beta in cell signaling pathways and the potential usage for the treatment of elevated level of GSK-3 beta involved diseases.
Bioorganic & Medicinal Chemistry 03/2004; 12(5):1239-55. · 2.92 Impact Factor
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Gee-Hong Kuo,
Catherine Prouty,
Alan DeAngelis,
Lan Shen,
David J O'Neill,
Chandra Shah,
Peter J Connolly,
William V Murray,
Bruce R Conway,
Peter Cheung,
Lori Westover,
Jun Z Xu,
Richard A Look,
Keith T Demarest,
Stuart Emanuel,
Steven A Middleton,
Linda Jolliffe, Mary Pat Beavers,
Xin Chen
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ABSTRACT: Attempts to design the macrocyclic maleimides as selective protein kinase C gamma inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors. Palladium-catalyzed cross-coupling reactions were used to synthesize the key intermediates 17 and 22 that resulted in the synthesis of novel macrocycles. All three macrocyclic series (bisindolyl-, mixed 7-azaindoleindolyl-, and bis-7-azaindolylmaleimides) were found to have submicromolar inhibitory potency at GSK-3beta with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3beta, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3beta, the additional nitrogen atoms in the indole rings may contribute to a significant degree. Overall, the bis-7-azaindolylmaleimides 28 and 29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound 29 almost behaved as a GSK-3beta specific inhibitor. Both 28 and 29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3beta selectivity of azaindolylmaleimides.
Journal of Medicinal Chemistry 10/2003; 46(19):4021-31. · 5.25 Impact Factor
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Gee-Hong Kuo,
Catherine Prouty,
Alan DeAngelis,
Lan Shen,
David J. O'Neill,
Chandra Shah,
Peter J. Connolly,
William V. Murray,
Bruce R. Conway,
Peter Cheung,
Lori Westover,
Jun Z. Xu,
Richard A. Look,
Keith T. Demarest,
Stuart Emanuel,
Steven A. Middleton,
Linda Jolliffe, Mary Pat Beavers,
Xin Chen
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ABSTRACT: Attempts to design the macrocyclic maleimides as selective protein kinase C γ inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors. Palladium-catalyzed cross-coupling reactions were used to synthesize the key intermediates 17 and 22 that resulted in the synthesis of novel macrocycles. All three macrocyclic series (bisindolyl-, mixed 7-azaindoleindolyl-, and bis-7-azaindolylmaleimides) were found to have submicromolar inhibitory potency at GSK-3β with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3β, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3β, the additional nitrogen atoms in the indole rings may contribute to a significant degree. Overall, the bis-7-azaindolylmaleimides 28 and 29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound 29 almost behaved as a GSK-3β specific inhibitor. Both 28 and 29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3β selectivity of azaindolylmaleimides.
08/2003;
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ABSTRACT: Rational design of small focused libraries that are biased toward specific therapeutic targets is currently at the forefront of combinatorial library design. Various structure-based design strategies can be implemented in focused library design when the 3D structure of the target is available through X-ray or NMR determination. This review discusses the major methods and programs specifically developed for the purpose of designing combinatorial libraries under the constraint of the binding site of a biological target, with emphasis on their advantages and disadvantages. Examples of the successful application of these methodologies are highlighted, demonstrating their performances within the practical drug discovery process.
Journal of Molecular Graphics and Modelling 07/2002; 20(6):463-8. · 2.18 Impact Factor
