Human papillomavirus (HPV), a life-threatening infection, is the leading cause of cancer mortality among women worldwide and needs for designing anticancerous drugs. In the present study, we explored specific novel inhibitors against E6 oncoprotein of high-risk HPV 16, known to inactivate tumor suppressor p53 protein. A homology model of HPV 16 E6 was built and validated using bioinformatics approach. A total of 5000 drug-like compounds were downloaded from ZINC database based on the properties similar to the known inhibitor Jaceosidin (5,7-dihydroxy-2-(4-hydroxy-3-methoxyphenyl)-6-methoxy-4H-chromen-4-one). Virtual-ligand-screening approaches were applied to screen appropriate drug-like compounds using molecular docking program AutoDock Vina in PyRx 0.8, and five best novel drug-like compounds were identified as potential competitive inhibitors against HPV 16 E6 compared to Jaceosidin. Two among these five identified most potential inhibitors, N-[(5-methyl-1H-benzimidazol-2-yl)methyl]-4-oxo-3,4-dihydrophthalazine-1-carboxamide and 6-[3-(3-fluoro-4-methyl-phenyl)-1,2,4-oxadiazol-5-yl]-1,4-dihydroquinoxaline-2,3-dione, were found to interact with E6 with binding energy of [Formula: see text] and [Formula: see text] kcal/mol, respectively, and form H-bonds with p53 binding site of E6 protein residues 113-122 (CQKPLCPEEK). These two inhibitors may help restoration of p53 functioning. The bioinformatics approach extends a promising platform for developing anticancerous competitive inhibitors targeting high-risk HPV 16.

2012-10-11·Journal of Medicinal Chemistry1区 · 医学

Optimization of a Small Tropomyosin-Related Kinase B (TrkB) Agonist 7,8-Dihydroxyflavone Active in Mouse Models of Depression

1区 · 医学

Article

作者: Liu, Xia ; Ye, Keqiang ; Luo, Hongbo R. ; Qi, Qi ; Xiao, Ge ; Chan, Chi-Bun ; He, Xiaolin

Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and to elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4'-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression.

2009-07-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

[N-methyl-³H₃]AZ10419369 Binding to the 5-HT_1BReceptor: In Vitro Characterization and in Vivo Receptor Occupancy

3区 · 医学

Article

作者: Maier, Donna L. ; Powell, Mark E. ; Jiang, Qiaoling ; Hill, Geraldine ; Ding, Min ; Pierson, M. Edward ; Elmore, Charles S. ; Heys, J. Richard ; Sobotka-Briner, Cindy ; Mrzljak, Ladislav

Radiotracers suitable for positron emission tomography studies often serve as preclinical tools for in vivo receptor occupancy. The serotonin 1B receptor (5-HT(1B)) subtype is a pharmacological target used to discover treatments for various psychiatric and neurological disorders. In psychiatry, 5-HT(1B) antagonists may provide novel therapeutics for depression and anxiety. We report on the in vitro and in vivo evaluation of tritiated 5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylicacid (4-morpholin-4-yl-phenyl)-amide ([N-methyl-(3)H(3)]AZ10419369), a potent 5-HT(1B) radiotracer. [N-methyl-(3)H(3)]-AZ10419369 showed saturable single-site high-affinity in vitro binding (guinea pig, K(d) = 0.38 and human, K(d) = 0.37) to guinea pig or human 5-HT(1B) receptors in recombinant membranes and high-affinity (K(d) = 1.9 nM) saturable (B(max) = 0.099 pmol/mg protein) binding in membranes from guinea pig striatum. When [N-methyl-(3)H(3)]AZ10419369 was administered to guinea pigs by intravenous bolus, the measured radioactivity was up to 5-fold higher in brain areas containing the 5-HT(1B) receptor (striatum/globus pallidus, midbrain, hypothalamus, and frontal cortex) compared with the cerebellum, the nonspecific binding region. Specific uptake peaked 30 min after injection with slow dissociation from target regions, as suggested by the in vitro binding kinetic profile. Pretreatment with 6-fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (AZD1134) and 2-aminotetralin (AR-A000002), 5-HT(1B)-selective ligands, inhibited [N-methyl-(3)H(3)]AZ10419369-specific binding in a dose-dependent manner. In the guinea pig striatum, AZD1134 (ED(50) = 0.017 mg/kg) occupies a greater percentage of the 5-HT(1B) receptors at a lower administered dose than AR-A000002 (ED(50) = 2.5 mg/kg). In vivo receptor occupancy is an essential component to build binding-efficacy-exposure relationships and compare novel compound pharmacology. [N-methyl-(3)H(3)]AZ10419369 is a useful preclinical tool for investigating 5-HT(1B) receptor occupancy for novel compounds targeting this receptor.

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适应症	最高研发状态	国家/地区	公司	日期
妇女多毛症	临床前	美国	Wyeth Research	2009-03-09
前列腺癌	临床前	美国	Wyeth Research	2009-03-09
子宫肌瘤	临床前	美国	Wyeth Research	2009-03-09