Advances in the optimization of the linker in proteolysis-targeting chimeras (PROTAC) / 药学学报

With high selectivity and potency, target protein degradation technology has recently emerged as a strategy for drug discovery and design. Proteolysis-targeting chimeras (PROTAC) function as inducers for the degradation of target proteins and are a research focus in drug development. Current research on PROTAC mainly revolves around the rational design of PROTAC molecules, the discovery of new E3 ubiquitin ligase ligands and improvement in drug targeting. In this review, we focus on the PROTAC linker and its effects on the generation of the E3 enzyme-PROTAC-target protein ternary complex from three standpoints: length, binding site and chemical properties. We discuss the influences of the linker on the efficacy and the selectivity of PROTAC molecules.

Operational models of allosteric modulation of G protein-coupled receptors / 药学学报

Since the Monod-Wyman-Changeux (MWC) model was initially proposed to explain the allosteric interactions between proteins and their ligands 50 years ago, there have been various models and hypotheses such as the induced-fit model on the interaction. These theoretical developments have been used broadly in the study of allosteric modulations of enzymes and receptors. In 1980, Lefkowitz and coworkers proposed a ternary complex model (TCM) for the regulatory mechanism of G protein-coupled receptors (GPCRs) that laid the theoretical foundation in the study of allosteric sites and ligands of GPCRs, the largest family of known receptors. The findings on how ligands interact with receptors to cause a functional response have significantly impacted the drug discovery field and accelerated the identification of allosteric modulators.

Investigations of polyethylene glycol mediated ternary molecular inclusion complexes of silymarin with beta cyclodextrins.

Objective To evaluate the effect of Polyethylene glycol and β-cyclodextrin on the solubility and dissolution of silymarin, a poorly water soluble herbal drug. Methodology Effects of beta cyclodextrins and Polyethylene glycol on solubility of silymarin were evaluated by phase solubility studies both separately as well as in combination. Solid inclusion complexes of silymarin –β-cyclodextrin in 1:1 molar ratio were prepared with and without polyethylene glycol by kneading method then evaluated for solubility dissolution and physical nature by XRD, FT-IR and NMR spectroscopy studies. Results The aqueous solubility of silymarin was linearly increased as a function of the concentration of β-cyclodextrin alone and in the presence of polyethylene glycol. Beta cyclodextrin formed molecular inclusion complexes with silymarin in1:1 molar ratio as revealed by phase solubility diagram. The ternary complexes of silymarin, β-cyclodextrin and polyethylene glycol demonstrated better dissolution than those of silymarin and its binary complexes with β-cyclodextrin alone. Silymarin - β-cyclodextrin complex caused 1.3 fold increase in the dissolution rate of silymarin, which was further increased up to 1.7 fold in presence of small amount of polyethylene glycol. Conclusion The presence of polyethylene glycol markedly enhances the molecular complexation and solubilizing efficiencies of β-cyclodextrin on silymarin.

Formulation and characterization of ternary complex of poorly soluble duloxetine hydrochloride.

Duloxetine hydrochloride (DXH) suffers from poor solubility and thereby poor absorption, which ultimately leads to poor bioavailability. In present study, an attempt has been made to formulate and characterize duloxetine hydrochloride (DXH) complex, using β-cyclodextrin (β-CD) and different hydrophilic polymers in order to enhance its solubility and dissolution rate. Phase solubility study was used to investigate the interaction of the drug in binary systems (DXH-β-CD) as well as ternary systems (DXH-β-CD-hydrophilic polymer). It was observed that solubilization of DXH by β-CD was further enhanced by using HPMC K4M at 0.1% w/v concentration. Several methods were used to prepare ternary complex of DXH-β-CD-HPMC K4M. Ternary complex prepared by co-evaporation method containing DXH-β-CD-HPMC K4M in the ratio of 1:1.10:0.01 has shown the fastest dissolution rate (53.65 ± 2.83% in 5 min) as compared to pure DXH (3.03 ± 1.88% in 5 min) as well as other methods used to prepare these complexes. The prepared ternary complex system was characterized by the help of X-ray powder diffraction studies, differential scanning calorimetry and scanning electron microscopy. It was observed that enhancement in solubility as well as dissolution rate of DXH was due to formation of ternary complex system.

The effect of ternary complex factor Net on the proliferation of human pancreatic carcinoma cell line BxPC3 / 中华胰腺病杂志

Objective To investigate the expression of the ternary complex factor Net in human pancreatic carcinoma cell line BxPC3 and its effect on cell proliferation and the expression of c-fos.Methods pEGFP-Net prokaryotic expression plasmid and empty vector pEGFP were transfed into BxPC3 cens by using lipofectamine 2000,then monoclonal cell which stably expressing Net was established.Human pancreatic carcinoma cells proliferation was detected by MTT and flow cytometry.The tuRNA and protein expression of Net and c-fos in BxPC3 cells were detected by real.time PCR and Western blot.Results Net was low expressed in BxPC3 cells.After pEGFP-Net transfection,Net wag stably expressed and the expression of c-fos was inhibited,cell proliferation was also inhibited after pEGFP-Net transfection,the inhibitory rates at the 3rd, 5th,7th day was 38.81%,55.34%and 56.92%respectively,which were significantly higher than those in the empty vector group(5.09%,12.42%,8.6%,P<0.05).G_0/G_1 phase cell was(61.79±5.67)%,which were significantly higher than(45.14±3.37)%in the empty vector group(P<0.05).Conclusions The ternary complex factor Net could inhibit pancreatic carcinoma cell line BxPC3 proliferation.Its mechanism was possibly repressing expression of oncogene c-fos.

The Stability of Glucosamine-?-Aminoacids-Nickel(Ⅱ) Ternary Complexes / 中国药房

OBJECTIVE: To studies on the stability of glucosamine-?-aminoacids-nickel(Ⅱ) ternary complexes(GANTC). METHODS: The formation constant of GANTC were determined at (25?0.1) ℃,I=0.1 mol?L-1 KNO3 by pH method. RESULTS: The formation constant of GANTC were Gly 13.73(7.33),Pro 13.97(7.12),Ser 13.15(7.07),Val 13.46(6.84),iLe 13.55(6.88),Phe 13.13(6.93) and Met 13.17(7.18). CONCLUSIONS: The two biologically active ligand,?-aminoacid and glucosamine accommodate each other when coordinated to nickel(Ⅱ) ion. The formation constant of the ternary complexes linearly increase with the increase of protonation constant of aminoacid. Linear free energy relationship does exist in the presence of ternary system.

Synthesis and Properties Study of Ternary Complex of Rare Earth with L-Leucine and Imidazoles / 中国药房

OBJECTIVE:To synthesize ternary complex of rare earth with L-Leucine and imidazoles and to determine its properties.METHODS:The ternary solid complex was synthesized from the reaction of rare earth chlorate with L-Leucine and imidazoles in the medium of alcohol,and the compositional analysis,properties,mechanism of thermolysis,thermostability and the bacteriostatic action of the ternary complex were studied by chemistry analysis,chemical elements analysis,infrared spectral(IR)analysis,molar conductivity measurement and derivative thermogravimetry(TG-DTG)analysis,bioactivity experiments etc.RESULTS:The constitute structure of the ternary complexes was detected to be electrolyte1∶3type RE(Leu) 3 Im(H 2 O)Cl 3 ?2H 2 O,meanwhile,the thermolysis dynamics,thermostability and the bacteriostatic action against E coli of the ternary complex were established preliminarily.CONCLUSION:The composition and the property of the ternary complexes are stable and which were found to be of good bacteriostatic action in the preliminary examination.