Author: Zheng, Yong-Tang ; Xu, Xiao-Shuang ; Chang, Shan ; Bedwell, Gregory J ; Zhang, Da-Wei ; Engelman, Alan N ; Yang, Liu-Meng ; Xu, Lei ; Luo, Rong-Hua

Due to its multifaceted essential roles in virus replication and extreme genetic fragility, the human immunodeficiency virus type 1 (HIV-1) capsid (CA) protein is a valued therapeutic target. However, CA is as yet unexploited clinically, as there are no antiviral agents that target it currently on the market. To facilitate the identification of potential HIV-1 CA inhibitors, we established a homogeneous time-resolved fluorescence (HTRF) assay to screen for small molecules that target a biologically active and specific binding pocket in the C-terminal domain of HIV-1 CA (CA CTD). The assay, which is based on competition of small molecules for the binding of a known CA inhibitor (CAI) to the CA CTD, exhibited a signal-to-background ratio (S/B) > 10 and a Z' value > 0.9. In a pilot screen of three kinase inhibitor libraries containing 464 compounds, we identified one compound, TX-1918, as a low micromolecular inhibitor of the HIV-1 CA CTD-CAI interaction (IC₅₀ = 3.81 μM) that also inhibited viral replication at moderate micromolar concentration (EC₅₀ = 15.16 μM) and inhibited CA assembly in vitro. Based on the structure of TX-1918, an additional compound with an antiviral EC₅₀ of 6.57 μM and cellular cytotoxicity CC₅₀ of 102.55 μM was obtained from a compound similarity search. Thus, the HTRF-based assay has properties that are suitable for screening large compound libraries to identify novel anti-HIV-1 inhibitors targeting the CA CTD.

05 Jul 2017·Anticancer ResearchQ4 · MEDICINE

Interactive Analysis of TX-1123 with Cyclo-oxygenase: Design of COX2 Selective TX Analogs

Q4 · MEDICINE

Article

Author: Kawaguchi, Yuki ; Hori, Hitoshi ; Tatematsu, Yohei ; Ohkura, Kazuto ; Uto, Yoshihiro

BACKGROUNDTo date, two cyclo-oxygenase (COX) isoforms, COX1 and COX2, have been identified. In the present study, the COX-inhibitory activities of TX-1123 derivatives with the 2-hydroxyarylidene-4-cyclopentene-1,3-dione structure were examined, and the binding profiles of TX-1123 to COXs were analyzed using docking simulations.MATERIALS AND METHODSX-Ray data on COX1 [protein data bank (PDB) ID=1PGG] and COX2 (PDB ID=3LN1) were used for molecular interactive simulations. The interactive profiles of TX-1123 derivatives with COXs were examined using a molecular simulation technique with Molegro Virtual Docker (CLC bio, Aarhus, Denmark).RESULTSTX-1123 exhibited COX1-inhibitory activity [half-maximal-inhibitory concentration (IC₅₀)=1.57×10^-5 M]. The COX2 inhibitory activity of TX-1123 was potent (IC₅₀=1.16×10^-6 M), and the ratio of COX1/COX2 inhibition was 13.5. TX-1123 bound to the COX2 molecule, and the oxygen atom of the 4-cyclopentene-1,3-dione region of TX-1123 interacted with Cys²⁶ and Gln⁴⁴⁷ of COX2.CONCLUSIONThe TX-1123-binding pocket of COX2 differs from that of the COX2-selective celecoxib-binding pocket. TX-1123 exhibited a different COX2-interactive mechanism from that of celecoxib.

01 Jul 2016·Anticancer research

An Antitumor 2-Hydroxyarylidene-4-cyclopentene-1,3-Dione as a Protein Tyrosine Kinase Inhibitor: Interaction Between TX-1123 Derivatives and Src Kinase.

Article

Author: Tatematsu, Yohei ; Kawaguchi, Yuki ; Hori, Hitoshi ; Ohkura, Kazuto ; Uto, Yoshihiro

BACKGROUNDProtein tyrosine kinases (PTKs) play major roles in signal transduction during cell proliferation and apoptosis. Tyrphostin AG17 was previously shown to be a potent tumor growth inhibitor, while AG17 induced apoptosis and inhibited activity of cyclin-dependent kinase 2. We herein describe the binding features of tyrphostin AG17 analogs, such as TX-1123, with Src kinase (Src-K).MATERIALS AND METHODSStructural data for Src-K were obtained from a protein data bank (ID=2SRC), and the molecular interactions between Src-K and TX-1123 derivatives were examined.RESULTSTX-1123 exihibited potent Src-K inhibitory activity (half maximal-inhibitory concentration=2.2 μM), and fit into the pocket of the Src-K molecule as well as c-AMP did.CONCLUSIONThe binding profiles of TX-1123 derivatives differed from each other, while their Src-K inhibitory activities were affected by their fit in the Src-K molecule.

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