1. An in silico protocol for identifying potential poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors from chemical databases
Miaomiao Niu, Yueqing Gu*. New J. Chem., 2015, 39, 1060—1066
PARP-1 inhibitors have been pursued for three decades. There are currently some PARP inhibitors in clinical trial development, including olaparib (AZD2281), which was the first PARP inhibitor tested in ovarian cancer patients, rucaparib (AG-014699), veliparib (ABT-888), and niraparib (MK4827). However, due to some problems such as poor solubility, toxicity, or low specificity, the clinical use of some of these organic PARP-1 inhibitors has been limited. Therefore, it is important to develop new PARP-1 inhibitors with novel modes of action.
Currently, most of the PARP-1 inhibitors under development mimic the nicotinamide moiety of NAD+.The development of such drugs is focused on how to identify novel PARP-1 inhibitors. Pharmacophore modeling is one of the most frequently used and valuable methods to discover novel scaffolds for various targets. To the best of our knowledge, there have been no studies on identification of PARP-1 inhibitors by pharmacophore search combining the molecular docking strategy.
2. Dynamic cytotoxic profiles of sulfur mustard in human dermal cells determined by multiparametric high-content analysis
Long Long, Wei Li, Wei Chen, Fei-Fei Li, Hua Li*, Li-Li Wang*. Toxicol. Res.,2016, 5,583–593
Treated manner of SM and candidate protective agents. All assays were conducted on both HEK-f and HDF-a cells. For all SM damage assays, SM was first dissolved in dimethyl sulfoxide (DMSO), and serially diluted in the cell culture medium to generate a 3× solution, which was soon added (in aliquots of 50 μl) to each well of 96-well assay plates containing preseeded cells. The final concentration of DMSO was strictly restricted to 0.2% across the entire assay. In the concentration-dependent experiments, three concentrations of SM (100, 300, and 450 μM) were used, and a single SM concentration of 300 μM was used in the time-course experiments. In all experiments, cell culture medium containing 0.2% DMSO was designated as the blank control, and was included in each plate to allow data normalization and plate quality control. Each test was performed in triplicate. After the addition of SM, the plates were returned to the cell culture incubator for a series of desired durations.
For anti-SM agent screening, the candidate protective agents (50 μl of 3× protective agents, including GSH, DP-7, Ola, ABT-888(veliparib), BSI-201, and HCQ) were added 1 h before 50 μl of 3×SM (900 μM)was treated for 48 h. Seven different concentrations of each protective agent and three repetitions for each test were used.
3. Design and discovery of 3-aryl-5-substituted-isoquinolin-1-ones as potent tankyrase inhibitors
Richard J. R. Elliott, Ashley Jarvis, Mohan B. Rajasekaran, Alan Ashworth*, Christopher J. Lord*. Med. Chem. Commun.,2015, 6,1687–1692
The ADP-ribosyltranferase diphtheria toxin-like (ARTD) or poly-ADP-ribose polymerase (PARP) protein superfamily comprises 17 proteins that contain a common catalytic domain. Those that are catalytically active use β-NAD+ as an essential co-factor to transfer poly- or mono-ADP-ribose units onto protein substrates. This post-translational modification is best characterised for PARP1 (ARTD1) and PARP2 (ARTD2) substrates, which play an important role in the DNA damage response. The PARP1/2 inhibitor olaparib has now been approved for use in the treatment of ovarian cancer, as it is able to selectively target tumour cells with either a BRCA1 or BRCA2 tumour suppressor gene defect. PARP1/2 inhibitors such as olaparib 1 and veliparib 2 exploit the nicotinamidyl pharmacophore present in β-NAD+ 3. Tankyrase 1 and 2 (TNKS/ARTD5 & TNKS2/ARTD6) are PARP proteins which are involved in a range of cellular functions including telomere maintenance, control of the mitotic checkpoint and WNT signalling, as well as the genetic disorder Cherubism.
