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Ouyang Q.,Computational Chemical Genomics Screening Center | Ouyang Q.,Chongqing Medical University | Nguyen K.N.,Washington University in St. Louis | Wang L.,Computational Chemical Genomics Screening Center | And 4 more authors.
Journal of Medicinal Chemistry

Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3- TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues. © 2014 American Chemical Society. Source

Wang X.,Bengbu Medical College | Zhang J.-J.,Bengbu Medical College | Sun Y.-M.,Bengbu Medical College | Zhang J.,Bengbu Medical College | And 3 more authors.
Folia Biologica (Czech Republic)

The purpose of the study was to evaluate the anti-tumour effects of triptolide (TPL) and of the combination of TPL and cisplatin (DDP) in DDP-resistant HNE1/DDP nasopharyngeal cancer (NPC) cells and to reveal the possible mechanisms. HNE1/DDP cells were treated with TPL and/or DDP. Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and colony-forming assay; the combination index of the synergism between TPL and DDP was calculated. Cell morphological changes were observed under a microscope. Reactive oxygen species (ROS) and apoptosis rate were determined by flow cytome-try. 5,5',6,6'-tetrachloro-1,1',3,3'-tetrethyl benzimidalyl carbocyanine iodide (JC-1) staining was used to determine mitochondrial membrane potential (MMP). Protein expression was analysed by Western blot, including Bax, caspase-9, Bcl-2, Mcl-1. TPL had an obvious anti-tumour effect and exhibited synergistic cytotoxicity with DDP on DDP-resistant HNE1/DDP cells. TPL induced HNE1/DDP cell apoptosis via inducing ROS generation. This effect was abolished by the inhibitor of ROS, N-acetyl-L-cysteine (NAC). TPL alone or combined with DDP could lower MMP significantly. Western blot showed that TPL alone or in combination with DDP increased expression of Bax and caspase-9, but reduced expression of Bcl-2 and Mcl-1. We conclude that TPL could induce cell apoptosis and synergize with DDP by regulating ROS generation and mitochondrial pathways in HNE1/DDP cells. This indicates that TPL may be effective in DDP-resistant NPC, either alone or combined with DDP. Source

Ouyang Q.,Computational Chemical Genomics Screening Center | Ouyang Q.,University of Pittsburgh | Ouyang Q.,Chongqing Medical University | Tong Q.,Computational Chemical Genomics Screening Center | And 9 more authors.
ACS Medicinal Chemistry Letters

An extensive exploration of the structure-activity relationship of a trisubstituted sulfonamide series led to the identification of 39, which is a potent and selective CB2 receptor inverse agonist [K i(CB2) = 5.4 nM, and Ki(CB1) = 500 nM]. The functional properties measured by cAMP assays indicated that the selected compounds were CB2 inverse agonists with high potency values (for 34, EC50 = 8.2 nM, and for 39, EC50 = 2.5 nM). Furthermore, an osteoclastogenesis bioassay indicated that trisubstituted sulfonamide compounds showed great inhibition of osteoclast formation. © 2013 American Chemical Society. Source

Gao Y.,Institute of Hematology | Yang P.,Computational Chemical Genomics Screening Center | Yang P.,University of Pittsburgh | Shen H.,University of Pittsburgh | And 28 more authors.
Nature Communications

Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC. © 2015 Macmillan Publishers Limited. Source

Myint K.-Z.,Carnegie Mellon University | Myint K.-Z.,Computational Chemical Genomics Screening Center | Myint K.-Z.,University of Pittsburgh | Wang L.,Computational Chemical Genomics Screening Center | And 5 more authors.
Molecular Pharmaceutics

In this manuscript, we have reported a novel 2D fingerprint-based artificial neural network QSAR (FANN-QSAR) method in order to effectively predict biological activities of structurally diverse chemical ligands. Three different types of fingerprints, namely, ECFP6, FP2 and MACCS, were used in FANN-QSAR algorithm development, and FANN-QSAR models were compared to known 3D and 2D QSAR methods using five data sets previously reported. In addition, the derived models were used to predict GPCR cannabinoid ligand binding affinities using our manually curated cannabinoid ligand database containing 1699 structurally diverse compounds with reported cannabinoid receptor subtype CB2 activities. To demonstrate its useful applications, the established FANN-QSAR algorithm was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds, and we have discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. To the best of our knowledge, this is the first report for a fingerprint-based neural network approach validated with a successful virtual screening application in identifying lead compounds. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. © 2012 American Chemical Society. Source

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