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Promising Drug Target (promising + drug_target)
Selected AbstractsBipolar disorder: candidate drug targets,MOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 3 2008Carlos A. Zarate Jr Abstract Current pharmacotherapy for bipolar disorder is generally unsatisfactory for a large number of patients. Even with adequate modern bipolar pharmacological therapies, many afflicted individuals continue to have persistent mood episode relapses, residual symptoms, functional impairment, and psychosocial disability. Creating novel therapeutics for bipolar disorder is urgently needed. Promising drug targets and compounds for bipolar disorder worthy of further study include both systems and intracellular pathways and targets. Specifically, the purinergic system, the dynorphin opioid neuropeptide system, the cholinergic system (muscarinic and nicotinic systems), the melatonin and serotonin [5-hydroxytryptamine receptor 2C] system, the glutamatergic system, and the hypothalamic-pituitary adrenal axis have all been implicated. Intracellular pathways and targets worthy of further study include glycogen synthase kinase-3 protein, protein kinase C, and the arachidonic acid cascade. Mt Sinai J Med 75:225,246, 2008. © 2008 Mount Sinai School of Medicine [source] Signal Transduction Pathways Involved in Brain Death-Induced Renal InjuryAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009H. R. Bouma Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to endothelial dysfunction and the release of cytokines in the circulation. Serum levels of interleukin-6, -8, -10, and monocyte chemoattractant protein-1 (MCP-1) are increased after brain death. Binding with cytokine-receptors in kidneys stimulates activation of nuclear factor-kappa B (NF-,B), selectins, adhesion molecules and production of chemokines leading to cellular influx. Mitogen-activated protein kinases (MAP-kinases) mediate inflammatory responses and together with NF-,B they seem to play an important role in brain death induced renal injury. Altering the activation state of MAP-kinases could be a promising drug target for early intervention to reduce cerebral injury related donor kidney damage and improve outcome after transplantation. [source] Crystallization and preliminary crystallographic analysis of cyanide-insensitive alternative oxidase from Trypanosoma brucei bruceiACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010Yasutoshi Kido Cyanide-insensitive alternative oxidase (AOX) is a mitochondrial membrane protein and a non-proton-pumping ubiquinol oxidase that catalyzes the four-electron reduction of dioxygen to water. In the African trypanosomes, trypanosome alternative oxidase (TAO) functions as a cytochrome-independent terminal oxidase that is essential for survival in the mammalian host; hence, the enzyme is considered to be a promising drug target for the treatment of trypanosomiasis. In the present study, recombinant TAO (rTAO) overexpressed in haem-deficient Escherichia coli was purified and crystallized at 293,K by the hanging-drop vapour-diffusion method using polyethylene glycol 400 as a precipitant. X-ray diffraction data were collected at 100,K and were processed to 2.9,Å resolution with 93.1% completeness and an overall Rmerge of 9.5%. The TAO crystals belonged to the orthorhombic space group I222 or I212121, with unit-cell parameters a = 63.11, b = 136.44, c = 223.06,Å. Assuming the presence of two rTAO molecules in the asymmetric unit (2 × 38,kDa), the calculated Matthews coefficient (VM) was 3.2,Å3,Da,1, which corresponds to a solvent content of 61.0%. This is the first report of a crystal of the membrane-bound diiron proteins, which include AOXs. [source] Structure of the synthetase domain of human CTP synthetase, a target for anticancer therapyACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 7 2006Maria Ehn Cytidine triphosphate synthetase (CTPS) is a key enzyme in nucleic acid and phospholipid biosynthesis and its activity is increased in certain human cancers, making it a promising drug target. The crystal structure of the synthetase domain of human CTPS, which represents the first structure of a CTPS from an eukaryote, has been determined. The structure is homotetrameric and each active site is formed by three different subunits. Sulfate ions bound to the active sites indicate the positions of phosphate-binding sites for the substrates ATP and UTP and the feedback inhibitor CTP. Together with earlier structures of bacterial CTPS, the human CTPS structure provides an extended understanding of the structure,function relationship of CTPS-family members. The structure also serves as a basis for structure-based design of anti-proliferative inhibitors. [source] KATP channel openers: Structure-activity relationships and therapeutic potentialMEDICINAL RESEARCH REVIEWS, Issue 2 2004Raimund Mannhold Abstract ATP-sensitive potassium channels (KATP channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. KATP channels were identified in a variety of tissues including muscle cells, pancreatic ,-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, KATP channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via KATP channels. Given their many physiological functions, KATP channels represent promising drug targets. Sulfonylureas like glibenclamide block KATP channels; they are used in the therapy of type 2 diabetes. Openers of KATP channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols. © 2003 Wiley Periodicals, Inc. Med Res Rev, 24, No. 2, 213,266, 2004 [source] Current Progress in the Fatty Acid Metabolism in Cryptosporidium parvum,THE JOURNAL OF EUKARYOTIC MICROBIOLOGY, Issue 4 2004GUAN ZHU ABSTRACT Cryptosporidium parvum is one of the apicomplexans that can cause severe diarrhea in humans and animals. The slow development of anti-cryptosporidiosis chemotherapy is primarily due to the poor understanding on the basic metabolic pathways in this parasite. Many well-defined or promising drug targets found in other apicomplexans are either absent or highly divergent in C. parvum. The recently discovered apicoplast and its associated Type n fatty acid synthetic enzymes in Plasmodium, Toxoplasma, and Eimeria apicomplexans are absent in C. parvum, suggesting this parasite is unable to synthesize fatty acids de novo. However, C. parvum possesses a giant Type I fatty acid synthase (CpFASl) that makes very long chain fatty acids using mediate or long chain fatty acids as precursors. Cryptosporidium also contains a Type I polyketide synthase (CpPKSl) that is probably involved in the production of unknown polyketide(s) from a fatty acid precursor. In addition to CpFASl and CpPKSl, a number of other enzymes involved in fatty acid metabolism have also been identified. These include a long chain fatty acyl elongase (LCE), a cytosolic acetyl-CoA carboxylase (ACCase), three acyl-CoA synthases (ACS), and an unusual "long-type" acyl-CoA binding protein (ACBP), which allows us to hypothetically reconstruct the highly streamlined fatty acid metabolism in this parasite. However, C. parvum lacks enzymes for the oxidation of fatty acids, indicating that fatty acids are not an energy source for this parasite. Since fatty acids are essential components of all biomembranes, molecular and functional studies on these critical enzymes would not only deepen our understanding on the basic metabolism in the parasites, but also point new directions for the drug discovery against C. parvum and other apicomplexan-based diseases. [source] Lysosomal cysteine proteases (cathepsins): promising drug targetsACTA CRYSTALLOGRAPHICA SECTION D, Issue 2 2003an Turk Papain-like lysosomal cysteine proteases are processive and digestive enzymes expressed in organisms from bacteria to humans. Their ubiquity alone makes them potential drug targets, with the assumption that appropriate specificities may be achieved. These enzymes have rather short active-site clefts, comprising three well defined substrate-binding subsites (S2, S1 and S1,) and additionally have comparatively broad binding areas (S4, S3, S2,, S3,). This geometry distinguishes them from other protease classes, such as serine and aspartic proteases, with six and eight substrate-binding sites, respectively. Exopeptidases (cathepsins B, C, H and X), in contrast to endopeptidases (such as cathepsins L, S, V and F), possess structural features that facilitate binding of N- and C-terminal groups of substrates in the active-site cleft. Other than a clear preference for free chain termini in the case of exopeptidases, the substrate-binding sites exhibit no strict specificities. Instead, their subsite preferences arise more from specific exclusions of substrate type. This presents a challenge for the design of inhibitors to target a specific cathepsin: only the cumulative effect of an assembly of inhibitor fragments can produce the desired result. The small number of papain-like lysosomal cysteine proteases (11 human enzymes are known) and the small number of substrate-binding sites calls for a innovative and empirical approach. [source] | |||||||||||||