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1.  Virtual Screening against Acetylcholine Binding Protein 
Journal of biomolecular screening  2011;17(2):204-215.
The nicotinic acetylcholine receptors (nAChRs) are a member of the ligand-gated ion channel family and play a key role in the transfer of information across neurological networks. The X-ray crystal structure of agonist-bound α7 acetylcholine binding protein (AChBP) has been recognized as the most appropriate template to model the ligand-binding domain of nAChR for studying the molecular mechanism of the receptor–ligand interactions. Virtual screening of the National Cancer Institute diversity set, a library of 1990 compounds with nonredundant pharmacophore profiles, using AutoDock against AChBPs revealed 51 potential candidates. In vitro radioligand competition assays using [3H] epibatidine against the AChBPs from the freshwater snails, Lymnaea stagnalis, and from the marine species, Aplysia californica and the mutant (AcY55W), revealed seven compounds from the list of candidates that had micromolar to nanomolar affinities for the AChBPs. Further investigation on α7nAChR expressing in Xenopus oocytes and on the recombinant receptors with fluorescence resonance energy transfer (FRET)–based calcium sensor expressing in HEK cells showed that seven compounds were antagonists of α7nAChR, only one compound (NSC34352) demonstrated partial agonistic effect at low dose (10 μM), and two compounds (NSC36369 and NSC34352) were selective antagonists on α7nAchR with moderate potency. These hits serve as novel templates/scaffolds for development of more potent and specific in the AChR systems.
doi:10.1177/1087057111421667
PMCID: PMC4762448  PMID: 21956172
ligand binding; receptor binding; docking; virtual screening; α7 acetylcholine binding protein
2.  Interruptin B induces brown adipocyte differentiation and glucose consumption in adipose-derived stem cells 
Molecular Medicine Reports  2016;13(3):2078-2086.
Interruptin B has been isolated from Cyclosorus terminans, however, its pharamcological effect has not been fully identified. In the present study, the effects of interruptin B, from C. terminans, on brown adipocyte differentiation and glucose uptake in adipose-derived stem cells (ASCs) were investigated. The results revealed that interruptin B dose-dependently enhanced the adipogenic differentiation of ASCs, with an induction in the mRNA expression levels of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ. In addition, interruptin B efficiently increased the number and the membrane potential of mitochondria and upregulated the mRNA expression levels of uncoupling protein (UCP)-1 and cyclooxygenase (COX)-2, which are all predominantly expressed in brown adipocytes. Interruptin B increased glucose consumption in differentiated ASCs, accompanied by the upregulation in the mRNA expression levels of glucose transporter (GLUT)-1 and GLUT-4. The computational analysis of molecular docking, a luciferase reporter assay and surface plasmon resonance confirmed the marked binding affinity of interruptin B to PPAR-α and PPAR-γ (KD values of 5.32 and 0.10 µM, respectively). To the best of our knowledge, the present study is the first report to show the stimulatory effects of interruptin B on brown adipocyte differentiation and glucose uptake in ASCs, through its role as a dual PPAR-α and PPAR-γ ligand. Therefore, interruptin B could be further developed as a therapeutic agent for the treatment of diabetes.
doi:10.3892/mmr.2016.4758
PMCID: PMC4769002  PMID: 26781331
interruptin B; Cyclosorus terminans; adipose-derived stem cell; brown adipocyte; peroxisome proliferator-activated receptors; glucose uptake
3.  Virtual Screening Against α-Cobratoxin 
Journal of biomolecular screening  2009;14(9):1109-1118.
α-Cobratoxin (Cbtx), the neurotoxin isolated from the venom of the Thai cobra Naja kaouthia, causes paralysis by preventing acetylcholine (ACh) binding to nicotinic acetylcholine receptors (nAChRs). In the current study, the region of the Cbtx molecule that is directly involved in binding to nAChRs is used as the target for anticobratoxin drug design. The crystal structure (1YI5) of Cbtx in complex with the acetylcholine binding protein (AChBP), a soluble homolog of the extracellular binding domain of nAChRs, was selected to prepare an α-cobratoxin active binding site for docking. The amino acid residues (Ser182-Tyr192) of the AChBP structure, the binding site of Cbtx, were used as the positive control to validate the prepared Cbtx active binding site (root mean square deviation < 1.2 Å). Virtual screening of the National Cancer Institute diversity set, a library of 1990 compounds with nonredundant pharmacophore profiles, using AutoDock against the Cbtx active site, revealed 39 potential inhibitor candidates. The adapted in vitro radioligand competition assays using [3H]epibatidine and [125I]bungarotoxin against the AChBPs from the marine species, Aplysia californica (Ac), and from the freshwater snails, Lymnaea stagnalis (Ls) and Bolinus truncates (Bt), revealed 4 compounds from the list of inhibitor candidates that had micromolar to nanomolar interferences for the toxin binding to AChBPs. Three hits (NSC42258, NSC121865, and NSC134754) can prolong the survival time of the mice if administered 30 min before injection with Cbtx, but only NSC121865 and NSC134754 can prolong the survival time if injected immediately after injection with Cbtx. These inhibitors serve as novel templates/scaffolds for the development of more potent and specific anticobratoxin.
doi:10.1177/1087057109344617
PMCID: PMC3191909  PMID: 19734437
α-cobratoxin; virtual screening; docking; neurotoxin; nicotinic acetylcholine receptor

Results 1-3 (3)