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Chemicals/CAS: benomyl, 17804-35-2; carbon 14, 14762-75-5; colchicine, 64-86-8; fuberidazole, 3878-19-1; griseofulvin, 126-07-8; mebendazole, 31431-39-7; melatonin, 73-31-4; nocodazole, 31430-18-9; parbendazole, 14255-87-9; podophyllotoxin, 518-28-5; tiabendazole, 148-79-8; vinblastine, 865-21-4; Benzimidazoles; Carbamates; Colchicine, 64-86-8; Glycoproteins; Griseofulvin, 126-07-8; Melatonin, 73-31-4; Podophyllotoxin, 518-28-5; Receptors, Drug; Tubulin; Vinblastine, 865-21-4

Chemicals/CAS: benomyl, 17804-35-2; carbon 14, 14762-75-5; colchicine, 64-86-8; fuberidazole, 3878-19-1; griseofulvin, 126-07-8; mebendazole, 31431-39-7; melatonin, 73-31-4; nocodazole, 31430-18-9; parbendazole, 14255-87-9; podophyllotoxin, 518-28-5; tiabendazole, 148-79-8; vinblastine, 865-21-4; Benzimidazoles; Carbamates; Colchicine, 64-86-8; Glycoproteins; Griseofulvin, 126-07-8; Melatonin, 73-31-4; Podophyllotoxin, 518-28-5; Receptors, Drug; Tubulin; Vinblastine, 865-21-4

The effects of nine drugs on the CD spectra of a synthetic calcium binding analog of site III or rabbit skeletal troponin C, can generally be divided into 3 groups: (1) that consisting of haloperidol, benperidol, molindone and promethazine, had no effect on the CD spectrum or calcium sensitivity of the apopeptide; (2) that composed of structurally rigid thioxanthenes, induced CD-detectable structural change in the apopeptide but prevented Ca2+-induced structural change; (3) that consisting of chlorpromazine, trifluoperazine and fluphenazine, induced structural change in the peptide but had no effect on the Ca2+-induced structural change.

The present study was undertaken as a step to delineate further the localization of the calcium-binding sites in fibrinogen and to assess the anticlotting properties of fibrinogen degradation products. To this purpose, fragments Y were prepared by plasmin digestion of human fibrinogen in the presence of added Ca2+, and purified. We found that, on a molar basis, fragments Y exhibit twice as much anticlotting activity as fragments X. They possess two calcium-binding sites with K(d) = 1.9 x 10-5 M. Their predominant amino-terminal amino acids are alanine and tyrosine. It is known that one binding site in fragment Y is related to its D moiety. We conclude that the other calcium-binding site may be located in the central domain of the molecule. Chemicals/CAS: alanine, 56-41-7, 6898-94-8; calcium, 7440-70-2; fibrinogen, 9001-32-5; plasmin, 9001-90-5, 9004-09-5; tyrosine, 16870-43-2, 55520-40-6, 60-18-4; Calcium, 7440-70-2; Fibrin Fibrinogen Degradation Products; fibrinogen fragment Y; Fibrinogen, 9001-32-5; Plasmin, EC 3.4.21.7

At the molecular level, the activity of drugs relies on a sequence of biorecognition phenomena, such as the binding to biological macromolecules, which define their pharmacological, toxicological and pharmacokinetic profiles. Physiologically-relevant interactions are usually very stereospecific: the occurrence of high binding affinities for specific stereochemical configurations or conformational arrangements of a drug is a very important research topic in the field of medicinal chemistry. When a drug is bound with high affinity to its target or to a carrier protein, e.g. a serum albumin, the conformational restraint due to the interaction may result in the insurgence of induced circular dichroism (ICD), which can be detected experimentally by spectroscopic analysis: nice examples are given by the ICD spectra of diazepam and ketoprofen complexed with human serum albumin (HSA). [1] Quantum mechanical (QM) calculations based on time-dependent density functional theory (TD-DFT) can be used to investigate the theoretical ICD spectra of all the possible conformational arrangements of the ligand, and may result very helpful in the identification of possible binding modes. [2] The present communication will report the application of TD-DFT calculations to the investigation of the binding modes of ketoprofen and benzodiazepines to serum albumins: in particular, the stereospecific binding of the M conformation of benzodiazepines to HSA is confirmed, and the peculiar species-dependent ICD spectra observed for the binding of ketoprofen to different serum albumins can be explained by the selection of different mutual arrangements of the phenyl moieties in the binding pockets. [1] M. Pistolozzi, C. Bertucci, Chirality 20, 552 (2008). [2] S. Ionescu, I. Matei, C. Tablet, M. Hillebrand, Phys. Chem. Chem. Phys. 15, 11604 (2013).

Native liquid extraction surface analysis (LESA) mass spectrometry enables the direct sampling of protein complexes from a solid surface. We have previously demonstrated native LESA mass spectrometry of holomyoglobin (∼17kDa) from glass slides and tetrameric haemoglobin (∼64kDa) from dried blood spots and thin tissue sections. Here, we further explore the capabilities of this emerging technique by investigating a range of proteins which exist in various oligomeric states in vivo. Tetrameric avidin (∼64kDa), octameric (∼190kDa) and hexadecameric (∼380kDa) CS2 hydrolase, and tetradecameric GroEL (∼800kDa) were all detected by native LESA mass spectrometry. Moreover, trimeric AmtB, a membrane protein, could also be observed by native LESA mass spectrometry. The suitability of LESA mass spectrometry for probing protein-ligand binding was also investigated. Non-covalent complexes of the ligand biotin with the proteins avidin, haemoglobin and bovine serum albumin were detected. The results indicate that non-specific binding is minimal and that native LESA mass spectrometry is a promising tool for the investigation of biologically significant ligand binding.

The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an objective of minor importance. The usefulness of therapeutic drug monitoring (TDM) is not consequently investigated for new drugs. Usually the need for TDM is only discovered much later, when the drug is already on the market. TDM is particularly valuable under the following circumstances: (i) if there is a stronger relationship between the drug concentration and effect than between the dose and effect; (ii) if there is no simple and clear clinical parameter available to evaluate the clinical efficacy of the drug; (iii) if the therapeutic window is small; (iv) to document interactions; (v) to monitor drug compliance; and (vi) if there is large intra- and interindividual variability and unpredictability in pharmacokinetic parameters. Our recommendation is that randomized concentration controlled trials should be performed during the early stages of drug development and that it should be obligatory for drug licensing. © 2008 Adis Data Information BV. All rights reserved.

// Kristin Beebe 1 , Mehdi Mollapour 1,7,8 , Bradley Scroggins 1 , Chrisostomos Prodromou 2 , Wanping Xu 1 , Mari Tokita 1 , Tony Taldone 3 , Lester Pullen 4 , Bettina K. Zierer 5 , Min-Jung Lee 6 , Jane Trepel 6 , Johannes Buchner 5 , Daniel Bolon 4 , Gabriela Chiosis 3 , Leonard Neckers 1 1 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 2 University of Sussex, John Maynard Smith Building, Falmer, Brighton, UK 3 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 4 University of Massachusetts Medical School, Department of Biochemistry and Molecular Pharmacology, Worcester, MA, USA 5 Technische Universitat Munchen, Department of Chemistry, Garching, Munich, Germany 6 Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 7 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA 8 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA Correspondence: Len Neckers, email: // Keywords : Hsp90, posttranslational modification, phosphorylation, drug binding, Hsp90 inhibitor Received : June 14, 2013 Accepted : July 5, 2013 Published : July 7, 2013 Abstract Heat shock protein 90 (Hsp90) is an essential molecular chaperone in eukaryotes that facilitates the conformational maturation and function of a diverse protein clientele, including aberrant and/or over-expressed proteins that are involved in cancer growth and survival. A role for Hsp90 in supporting the protein homeostasis of cancer cells has buoyed interest in the utility of Hsp90 inhibitors as anti-cancer drugs. Despite the fact that all clinically evaluated Hsp90 inhibitors target an identical nucleotide-binding pocket in the N domain of the chaperone, the precise determinants that affect drug binding in the cellular environment remain unclear, and it is possible that chemically distinct inhibitors may not share similar binding preferences. Here we demonstrate that two chemically unrelated Hsp90 inhibitors, the benzoquinone ansamycin geldanamycin and the purine analog PU-H71, select for overlapping but not identical subpopulations of total cellular Hsp90, even though both inhibitors bind to an amino terminal nucleotide pocket and prevent N domain dimerization. Our data also suggest that PU-H71 is able to access a broader range of N domain undimerized Hsp90 conformations than is geldanamycin and is less affected by Hsp90 phosphorylation, consistent with its broader and more potent anti-tumor activity. A more complete understanding of the impact of the cellular milieu on small molecule inhibitor binding to Hsp90 should facilitate their more effective use in the clinic.

Problem statement: Curcumin the active component of turmeric is known for its wide biological actions. Extensive studies on curcumin highlighted its anti-inflammatory, anti-oxidant, antimicrobial, anti-carcinogenic and anti-coagulant activity. The anti-inflammatory activities of curcumin have been demonstrated both in vitro and in vivo. Though curcumin and its anti-inflammatory properties are well documented, the exact mechanism of action and effective in vivo dosage required for potential anti-inflammatory activity of curcumin are yet to be determined. The current work reflects in identfying the the role curcumin in the inflmmatory cascade and arriving at an optimal effective dose (ED 50). Approach: The objective of the current study is to understand and establish the role of curcumin in the treatment of inflammatory condition, through in-silico, in-vitro and in-vivo studies. The specificity and binding affinity of curcumin to major inflammatory mediators such as, cytokines/chemokines, signaling proteins and transcription factors were evaluated using molecular docking. Subsequently, in-vitro experiments were conducted to establish the role of curcumin in reducing the release of histamine and ?-hexosaminidase form U937 human monocytes cell lines. Further, the Effective Dose (ED 50) of curcumin was established for its potent in vivo anti-inflammatory activity. Results: Our study confirmed a strong affinity of curcumin to various inflammatory mediators (ERK, PKC, P38 MAP Kinase, NFkB and Lipoxygenase). Curcumin when studied for its affinity towards chemokines/cytokines and TNF-? was found to be ineffective. Proportionate reduction in histamine and ?-hexosaminidase release in U937 cells in vitro and inhibition of paw edema in carrageenan induced inflammation in rats affirmed the dose dependent anti-inflammatory activity of curcumin. This in vivo study elucidated the ED 50 value to be 570.6 mg kg -1 body weight for curcumin, which apparently shall be the potent dose to screen its anti-inflammatory activity. Conclusion: Overall results suggest that, curcumin mediates its anti-inflammatory activity by its direct effect on multitarget inflammatory mediators while others were mediated by the downstream effects of curcumin. Curcumin can be a potent molecule in treatment of various diseases associated with inflammation, with its multi-target potency and high safety profile. � 2012 Science Publications.

Approximately one-third of the human proteome is made up of proteins that are entirely disordered or that contain extended disordered regions. Although these disordered proteins are closely linked with many major diseases, their binding mechanisms with small molecules remain poorly understood, and a major concern is whether their specificity can be sufficient for drug development. Here, by studying the interaction of a small molecule and a disordered peptide from the oncogene protein c-Myc, we describe a "specific-diffuse" binding mechanism that exhibits sequence specificity despite being of entropic nature. By combining NMR spectroscopy, biophysical measurements, statistical inference, and molecular simulations, we provide a quantitative measure of such sequence specificity and compare it to the case of the interaction of urea, which is diffuse but not specific. To investigate whether this type of binding can generally modify intermolecular interactions, we show that it leads to an inhibition of the aggregation of the peptide. These results suggest that the binding mechanism that we report may create novel opportunities to discover drugs that target disordered proteins in their monomeric states in a specific manner.