Advances on anti-neoplastic STAT3 inhibitors / 药学学报

Signal transducer and activator of transcription 3 (STAT3) is a kind of signal transduction protein involved in cell proliferation, differentiation, apoptosis and other important physiological processes in response to a large number of cytokines and growth factors in cells. It has been shown that constitutive activation of STAT3 is closely associated with oncogenesis and tumorigenesis. Inhibition of aberrant STAT3 signaling has been one of promising strategies for the development of anti-neoplastic therapeutics. The review summarizes the latest progress of STAT3 inhibitors in recent years from the perspective of targeting N-terminal domain, DNA binding domain, SH2 domain and C-terminal transactivation domain of STAT3.

Identification of novel selective TRPV3 antagonists based on virtual screening, molecular docking and bioassay / 药学学报

Transient receptor potential vanilloid member 3 (TRPV3) is a temperature-sensitive cation channel protein, which contributes to nociception, itch, hair growth, emotional control and the pathophysiology of migraine. However, research progress on TRPV3 fundamental molecular biology is rather slow, compared to other TRP channels due to the lack of its selective antagonists. It's necessary to identify TRPV3 selective antagonists for the study on TRPV3 physiological functions. In this study, several selective TRPV3 antagonists were identified by ligand-based virtual screening of shape-based similarity and electrostatic matching. The most potent one (V-39) blocked 2-APB-activated currents in a stable human TRPV3 expressed HEK293T cell line with IC50=18.0 ±1.1 μmol·L-1 (n=4). Besides, the interaction pattern between TRPV3 and its antagonists were studied through docking the antagonists into a homology model (TRPV3_HM4) generated from the crystal structure of TPRV1. The docking results show that the binding site of TRPV3 locates between linker domain (of N-terminus and TM1) and TRP Box. There are a π-π stacking interaction and hydrogen bonding interactions between compound V-39 and residues His-310, His-314 and Arg-577 of the pocket. Identification of these antagonists provides new probes for understanding the pharmacological function of TRPV3 channel.

Analysis of traditional Chinese medicine prescriptions based on support vector machine and analytic hierarchy process / 中国中药杂志

Combined use of drugs is a hot spot in the research of new drugs nowadays, and traditional Chinese medicine (TCM) is a classic practice in the combined use of drugs. In this paper, the compatibility of TCM prescriptions and the related properties of composed herbs were calculated and studied to verify and discuss the feasibility of the results in guiding compatibility. Research Group on New Drug Design, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences had established a structured database of TCM prescriptions by using traditional Chinese medicine inheritance support system (TCMISS V2.0), including 4 012 prescription compatibilities, 2 072 drug components, 381 kinds of TCM diseases, 316 kinds of TCM syndromes and 26 kinds of drug properties. On the basis of the created database above, Support Vector Machine (SVM) was used to analyze the prescription compatibility data and establish a model for predicting feasibility of drug compatibilities. Analytic Hierarchy Process (AHP) and cluster analysis were used to study the influence of drug properties in the rationality of prescription compatibility. The computational results showed that the accuracy in efficacy prediction of two data sets, i.e. prescription-disease and prescription-syndrome, was up to 90% in the linear SVM model. The macro₋averaging and micro₋averaging of the two models were around 0.92, 0.46, respectively. After AHP mapping, most of the incompatible combinations showed significant difference with other drug combinations during the clustering process in the vertical icicle, indicating that the proper machine learning algorithm can be used to lay the foundation for further exploring the combination rules in TCM and establishing more detailed drug-disease and syndrome predicting models, and provide theoretical guidance for the study of the combined use of drugs to a certain degree.

Construction of chemical information database based on optical structure recognition technique / 北京大学学报(医学版)

OBJECTIVE@#To create a protocol that could be used to construct chemical information database from scientific literature quickly and automatically.@*METHODS@#Scientific literature, patents and technical reports from different chemical disciplines were collected and stored in PDF format as fundamental datasets. Chemical structures were transformed from published documents and images to machine-readable data by using the name conversion technology and optical structure recognition tool CLiDE. In the process of molecular structure information extraction, Markush structures were enumerated into well-defined monomer molecules by means of QueryTools in molecule editor ChemDraw. Document management software EndNote X8 was applied to acquire bibliographical references involving title, author, journal and year of publication. Text mining toolkit ChemDataExtractor was adopted to retrieve information that could be used to populate structured chemical database from figures, tables, and textual paragraphs. After this step, detailed manual revision and annotation were conducted in order to ensure the accuracy and completeness of the data. In addition to the literature data, computing simulation platform Pipeline Pilot 7.5 was utilized to calculate the physical and chemical properties and predict molecular attributes. Furthermore, open database ChEMBL was linked to fetch known bioactivities, such as indications and targets. After information extraction and data expansion, five separate metadata files were generated, including molecular structure data file, molecular information, bibliographical references, predictable attributes and known bioactivities. Canonical simplified molecular input line entry specification as primary key, metadata files were associated through common key nodes including molecular number and PDF number to construct an integrated chemical information database.@*RESULTS@#A reasonable construction protocol of chemical information database was created successfully. A total of 174 research articles and 25 reviews published in Marine Drugs from January 2015 to June 2016 collected as essential data source, and an elementary marine natural product database named PKU-MNPD was built in accordance with this protocol, which contained 3 262 molecules and 19 821 records.@*CONCLUSION@#This data aggregation protocol is of great help for the chemical information database construction in accuracy, comprehensiveness and efficiency based on original documents. The structured chemical information database can facilitate the access to medical intelligence and accelerate the transformation of scientific research achievements.

A review of ANO1-based calcium activated chloride channel modulators / 药学学报

Calcium-activated chloride channel (CaCC) is an anion channel, widely distributed in the human body, taking a part in cell functions including secretion, heart muscle repolarization, nerve signal transmission and several physiological activities. The anoctamin 1 (ANO1) protein is the molecular basis of CaCC and the modification of ANO1 protein will produce a variety of pharmacological effects, such as analgesia, treating dysentery and asthma, even tumor proliferation and migration inhibition. In the past decade, many methods in screening of ANO1 regulators have been developed. Although a series of the ANO1-based CaCC regulatory molecules have been identified, the pharmacological effects of these molecules are not consistent. In this review, we introduce ANO1 protein regulators from many aspects including bio-test methods, structure-activity relationships, and the potential applications.

The structure-activity relationships of novel α7 nicotinic acetylcholine receptor agonists based on indolizine scaffold / 药学学报

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships (SAR). All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.60±0.19 μmol·L-1 and maximum effect (Emax) of 69.0%±2.8% compared with 3 mmol·L-1 ACh. Compound 17b with 8-cyclopropyl substitution shows an increased Emax of 81.1%±9.3% with EC50 at 2.74±0.74 μmol·L-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.

The synthesis of purine derivatives and its inhibitory activity on CD38 NADase / 药学学报

CD38 is a multifunctional enzyme expressed in a variety of mammalian tissues, its catalytic activity was involved in a wide range of physiological processes. Based on the reported inhibitor of human CD38 NADase, 33 purine derivatives were designed and synthesized. The biological activity assay showed that compounds 20 and 38 exhibited almost the same extent of inhibitory activities on human CD38 NADase as the lead compound H2. The results also revealed that small substituents at C-6 of purine ring gave no obvious effect on inhibitory activity, but phenylpropionyl moiety at N-2 could affect the binding mode of the compound with CD38. This study provides a reliable basis for future rational design of inhibitors for CD38.

Design, synthesis and biological assay of novel tripeptidic tetrazoles as inhibitors of 20S proteasome / 药学学报

Ubiquitin-proteasome pathway (UPP) is one of the ways utilized for selective degradation of many proteins in cells, and the 20S proteasome takes the functional machinery where hydrolysis of targeted proteins takes place. Based on existing peptide inhibitors, a series of novel tripeptidic tetrazoles have been designed, synthesized, and the structures have been confirmed with 1H NMR, MS and elemental analysis. Among them, three compounds (6b, 6d and 6h) showed inhibitory activities of ChT-L of 20S proteasome.