Search

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC50 = 0.032 μM for 1g against human URAT1 vs 7.20 μM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher’s randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.

The Visual Object Tracking challenge VOT2018 is the sixth annual tracker benchmarking activity organized by the VOT initiative. Results of over eighty trackers are presented; many are state-of-the-art trackers published at major computer vision conferences or in journals in the recent years. The evaluation included the standard VOT and other popular methodologies for short-term tracking analysis and a “real-time” experiment simulating a situation where a tracker processes images as if provided by a continuously running sensor. A long-term tracking subchallenge has been introduced to the set of standard VOT sub-challenges. The new subchallenge focuses on long-term tracking properties, namely coping with target disappearance and reappearance. A new dataset has been compiled and a performance evaluation methodology that focuses on long-term tracking capabilities has been adopted. The VOT toolkit has been updated to support both standard short-term and the new long-term tracking subchallenges. Performance of the tested trackers typically by far exceeds standard baselines. The source code for most of the trackers is publicly available from the VOT page. The dataset, the evaluation kit and the results are publicly available at the challenge website (http://votchallenge.net). Funding agencies: Slovenian research agencySlovenian Research Agency - Slovenia [P2-0214, P2-0094, J2-8175]; Czech Science FoundationGrant Agency of the Czech Republic [GACR P103/12/G084]; WASP; VR (EMC2); SSF (SymbiCloud); SNIC; AIT Strategic Research Programme 2017 Visua

Deep convolutional feature based Correlation Filter trackers have achieved record-breaking accuracy, but the huge computational complexity limits their application. In this paper, we derive the efficient convolution operators (ECO) tracker which obtains the top rank on VOT-2016. Firstly, we introduce a channel pruned VGG16 model to fast extract most representative channels for deep features. Then an Average Feature Energy Ratio method is put forward to select advantageous convolution channels, and an adaptive iterative strategy is designed to optimize object location. Finally, extensive experimental results on four benchmarks OTB-2013, OTB-2015, VOT-2016 and VOT-2017, demonstrate that our tracker performs favorably against the state-of-the-art methods.

Src-homology2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP-2) is a ubiquitously expressed protein-tyrosine phosphatase. SHP-2 is linked to human diseases and plays broad roles in cancer pathogenesis. Activity of the SHP-2 catalytic domain is auto-inhibited by an N-SH2 domain, maintaining SHP-2 in an inactive state. N-SH2 conformation switches to expose the catalytic domain, forming an active state. However, the switch mechanism is not clearly described. Although structural and kinetic studies in silicon have simulated the biological catalytic processes, Molecular Dynamics (MD) simulation has not provided sufficient information to explain the allosteric mechanism of SHP2. To further understand the conformational process, we created a novel method, solvent perturbed MD (SPMD), with high kinetic energy solvent to study SHP2 allosterism. We also illustrated the putative factor at the mouth of the opening pocket of SHP-2. We found, based on SPMD simulations, the distance between ASP61, of N-SH2 blocker, and ARG465 at the bottom of the pocket, reached 1 nm. Moreover, SPMD did not denature SHP2; the torsion angle and position of residue ARG465 in the bottom of the pocket were not significantly perturbed. Our SPMD simulation also demonstrated the periodic opening and closing of the blocker. Thus, our findings on the conformational alteration of SHP-2 in a solution interrupted system furthers our understanding of allosterism.

// Meiyan Wang 1,* , Xiaobo Li 1,2,* , Lei Dong 2,* , Xiubo Chen 3 , Weiren Xu 4 and Runling Wang 1 1 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China 2 Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA 3 Tianjin Medical University Eye Hospital, Tianjin, China 4 Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, China * These authors have contributed equally to this work Correspondence to: Runling Wang, email: // Keywords : PTP-MEG2 inhibitor; core hopping; diabetes; selectivity; molecular dynamics simulation; Gerotarget Received : March 22, 2016 Accepted : June 03, 2016 Published : June 30, 2016 Abstract Megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) is a tyrosine phosphatase expressed in megakaryocytic cells, and causes insulin sensitization when down regulated. Therefore, specific inhibitors of PTP-MEG2 are potential candidates for novel Type 2 Diabetes (T2DM)therapy. In this study, we discovered PTP-MEG2 inhibitors using high throughput and virtual screening (HTS/VS) and structural optimization in silicon .Eight compound-candidates were identified from the interactions with PTP-MEG2, protein tyrosine phosphatase 1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP). Results from enzymatic assays show compounds 4a and 4b inhibited PTP-MEG2 activity with an IC50 of 3.2 μM and 4.3 μM, respectively. Further, they showed a 7.5 and 5.5 fold change against PTP1B and TCPTP, respectively. We propose compounds 4a and 4b are PTP-MEG2 inhibitors with potential therapeutic use in T2DM treatment.

L-Rhamnulose (6-deoxy-L-arabino-2-hexulose) and L-fuculose (6-deoxy-L-lyxo-2-hexulose) were prepared from L-rhamnose and L-fucose by a two-step strategy. In the first reaction step, isomerization of L-rhamnose to L-rhamnulose, or L-fucose to L-fuculose was combined with a targeted phosphorylation reaction catalyzed by L-rhamnulose kinase (RhaB). The by-products (ATP and ADP) were selectively removed by silver nitrate precipitation method. In the second step, the phosphate group was hydrolyzed to produce L-rhamnulose or L-fuculose with purity exceeding 99% in more than 80% yield (gram scale).

Fluoride detection in aqueous solution has drawn much attention. Most fluoride probes are based on the cleavage of a silyl group by fluoride for the generation of fluorescence. However, such a reaction is generally slow in aqueous solution. Herein we successfully demonstrate the concept that increasing the hydrophilicity of a pendent group enhances the reactivity of a silyl-based probe for fluoride detection in aqueous solution. By applying this concept, we also developed a new probe with a pendent PEG unit (BW-F-204), which showed excellent fluoride sensing ability both in aqueous solution and in cell culture.

Visual tracking is a fundamental problem in computer vision. Recently, some methods have been developed to utilize features learned from a deep convolutional neural network for visual tracking and achieve record-breaking performances. However, deep trackers suffer from efficiency. In this paper, we propose an object tracking method combining the single-layer convolutional features with correlation filter to locate and speed up. Meanwhile accurate scale prediction and high-confidence model update strategy are adopted to solve the scale variation and similarity interfere problems. Extensive experiments on large scale benchmarks demonstrate the effectiveness of the proposed algorithm against state-of-the-art trackers.

Three series of prenylated and/or geranylated flavonoids were synthesized and evaluated for their α-glucosidase inhibitory activity. The 3',5'-digeranylated chalcone (16) was identified as a new α-glucosidase inhibitor whose activity (IC50=0.90 μM) was 50-fold more than that of acarbose (IC50=51.32 μM). Molecular docking studies revealed the existence of strong hydrophobic interaction and H-bonding between compound 16 and α-glucosidase's active site. The inhibitory mode analysis showed that 16 exhibited a competitive inhibitory mode.

A series of 6-hydroxyaurones and their analogues have been synthesized and evaluated for their in vitro α-glucosidase inhibitory and glucose consumption-promoting activity. These compounds exhibited varying degrees of α-glucosidase inhibitory activity, 11 of them showing higher potency than that of the control standard acarbose (IC50=50.30μM). Surprisingly, analogues devoid of a substituent at C-2 but having an aryl group at C-5 were found to be highly active (e.g., 7f, IC50=9.88μM). Docking analysis substantiated these findings. The kinetic analysis of compound 7f, the most potent α-glucosidase inhibitor of this study, revealed that it inhibited α-glucosidase in an irreversible and mixed competitive mode. In addition, compounds 7f and 10c exhibited significant glucose consumption promoting activity at 1μM.

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. Three series of tetracyclic oxindole derivatives were designed, synthesized and evaluated for α-glucosidase inhibitory activity in vitro. Compound 6t exhibited the most potent inhibitory activity with IC50 0.7 μM and was about 170 times as active as acarbose (IC50 = 115.8 μM). The kinetic analysis of compound 6t revealed it inhibited α-glucosidase in an irreversible and mixed manner. Fluorescence spectra indicated that 6t directly bound to α-glucosidase. Docking simulation showed the existence of potential H-bonding, van der Waals, Pi and Sigma-Pi interactions between 6t and α-glucosidase.

Lysine methyltransferase G9a regulates the transcription of multiple genes by primarily catalyzing mono- and di-methylation of histone H3 lysine 9, as well as several non-histone lysine sites. An attractive therapeutic target in treating leukemia, knockout studies of G9a in mice have found dramatically slowed proliferation and self-renewal of acute myeloid leukemia (AML) cells due to the attenuation of HoxA9-dependent transcription. In this study, a series of compounds were identified as potential inhibitors through structure-based virtual screening. Among these compounds, a new G9a inhibitor, DCG066, was confirmed by in vitro biochemical, and cell based enzyme assays. DCG066 has a novel molecular scaffold unlike other G9a inhibitors presently available. Similar to G9a’s histone substrate, DCG066 can bind directly to G9a and inhibit methyltransferase activity in vitro. In addition to suppressing G9a methyltransferase activity and reducing histone H3 methylation levels, DCG066 displays low cytotoxicity in leukemia cell lines with high levels of G9a expression, including K562. This work presents DCG066 as an inhibitor of G9a with a novel structure, providing both a lead in G9a inhibitor design and a means for probing the functionality of G9a.