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Chemical Biology & Drug Design

Prashant Joshi, Mehak Gupta, Ram A Vishwakarma, Ajay Kumar, Sandip B Bharate
Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases including Alzheimer's disease, cancer and diabetes mellitus. The present study was aimed to discover new scaffolds for GSK-3β inhibition, through protein-structure guided virtual screening approach. With the availability of large number of GSK-3β crystal structures with varying degree of RMSD in protein backbone and RMSF in side chain geometry; herein appropriate crystal structures were selected based on the characteristic ROC curve and percentage enrichment of actives...
November 29, 2016: Chemical Biology & Drug Design
Srinivasarao Kondaparla, Pooja Agarwal, Kumkum Srivastava, Sunil K Puri, S B Katti
A series of novel bisquinoline compounds comprising, N(1) -(7-chloroquinolin-4-yl) ethane-1,2-diamine and 7-chloro-N-(2-(piperazin-1-yl)ethyl)quinolin-4-amine connected with 7-chloro-4-aminoquinoline containing various amino acids is described. We have bio-evaluated the compounds against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum in vitro. Among the series, compounds 4 and 7 exhibited 1.8 and 10.6 fold superior activity as compared to chloroquine (CQ) (IC50 = 0...
November 29, 2016: Chemical Biology & Drug Design
Chuan Wang, Bin Shan, Qiong Wang, Qunyuan Xu, Hailin Zhang, Huimeng Lei
Voltage gated sodium channel NaV 1.7 serves an attractive target for chronic pain treatment. Several venom peptides were found to selectively inhibit NaV 1.7 but with intrinsic problems. Among them, Ssm6a, a recently discovered centipede venom peptide, shows the greatest selectivity against NaV 1.7, but dissociates from the target too fast and loses bioactivity in synthetic forms. As a disulfide-rich venom peptide, it is difficult to optimize Ssm6a by artificial mutagenesis and produce the peptide with common industrial manufacturing methods...
November 29, 2016: Chemical Biology & Drug Design
Fangjin Chen, Xiaolong Zhuo, Tan Qin, Xiao Guo, Chuanmao Zhang, Luhua Lai
Polo-like kinase 1 (Plk1), a member of polo-like kinase family, regulates multiple essential steps of the cell cycle progression. Plk1 is overexpressed in multiple cancer cell lines and considered to be a prime anticancer target. Plk1 accumulates in the nucleus during S and G2 phases by its bipartite nuclear localization signal (NLS) sequence, which is crucial for Plk1 regulation during normal cell cycle progression. Here, through combined computational and experimental studies, we identified compound D110, which inhibits Plk1 kinase activity with an IC50 of 85 nm and blocks the nuclear localization of Plk1 during S and G2 phases...
November 24, 2016: Chemical Biology & Drug Design
Cong-Jun Liu, Tao Zhang, Shu-Ling Yu, Xing-Jie Dai, Ya Wu, Jing-Chao Tao
Two series of novel acylthiosemicarbazide and oxadiazole fused-isosteviol derivatives were synthesized based on the 19-carboxyl modification. The target compounds were evaluated for their cytotoxicities against 3 cancer cell lines (HCT-116, HGC-27 and JEKO-1) using an MTT assay. Lead compounds from the acylthiosemicarbazides (4) showed IC50 values in the lower μmolar range. For example, compounds (4i, 4l, 4m, 4r and 4s) exhibited significant inhibitory activities against the 3 cell lines with IC50 values of 0...
November 23, 2016: Chemical Biology & Drug Design
Ashutosh Kumar, Tatsuro Kawamura, Makoto Kawatani, Hiroyuki Osada, Kam Y J Zhang
The human mutT homolog-1 (MTH1) protein prevents the incorporation of oxidized nucleotides such as 2-OH-dATP and 8-oxo-dGTP during DNA replication by hydrolyzing them into their corresponding monophosphates. It was found previously that cancer cells could tolerate oxidative stress due to this enzymatic activity of MTH1 and its inhibition could be a promising approach to treat several types of cancer. This finding has been challenged recently with increasing line of evidence suggesting that the cancer cell killing effects of MTH1 inhibitors may be related to their engagement of off-targets...
November 12, 2016: Chemical Biology & Drug Design
Chong-Zhen Qin, Qiao-Li Lv, Yan-Tao Yang, Jing-Min Zhang, Xiao-Jian Zhang, Hong-Hao Zhou
Previous studies have demonstrated that miRNAs play an important role in tumor development and progression. The role of miR-320d has been studied in several cancers except for glioma. The aim of the study was to investigate the expression levels, biological function, and mechanism of miR-320d in glioma. The expression levels of miR-320d were detected in glioma tissues and cell lines (U87 and U251) by RT-qPCR. Cell proliferation, colony formation, apoptosis, cell cycle and transwell assays were performed in glioma cell lines transfected with miR-320d mimics or controls to evaluate the effects of miR-320d in vitro...
November 12, 2016: Chemical Biology & Drug Design
Amandeep Singh, Christophe Biot, Albertus Viljoen, Christian Dupont, Laurent Kremer, Kewal Kumar, Vipan Kumar
Copper-catalyzed azide-alkyne [3 + 2] cycloaddition has been utilized for preparing a series of 1H-1,2,3-triazoles with the purpose of probing structure-activity relationships among a uracil-ferrocene-triazole conjugate family. The antitubercular evaluation studies revealed an improvement in activity with the introduction of a ferrocene nucleus among N-alkylazido-uracil precursors, with a preference for a bromo-substituent along with moderate chain lengths of n = 2-6. The reported protocol is a successful approach for integrating uracil-ferrocene-chalcone functionalities tethered via 1H-1,2,3-triazole rings with apparent physicochemical stability...
November 12, 2016: Chemical Biology & Drug Design
Sufang Zhao, Jingyu Zhu, Lei Xu, Jian Jin
Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase which is widely involved in cell signaling and controls a broad number of cellular functions. GSK3 contains α and β isoforms, and GSK3β has received more attention and becomes an attractive drug target for the treatment of several diseases. The binding pocket of Cyclin-dependent kinases 2 (CDK2) shares high sequence identity to that of GSK3β, and therefore the design of highly selective inhibitors towards GSK3β remains a big challenge...
November 11, 2016: Chemical Biology & Drug Design
Hong-Xia Li, Zhong-Chang Wang, Yu-Mei Qian, Xiao-Qiang Yan, Ya-Dong Lu, Hai-Liang Zhu
New series of chrysin derivatives (4a-4t) were designed and synthesized by introducing different substituted piperazines at C-7 position. Their inhibitory effects on FabH were evaluated using two Gram-negative bacterial strains, Escherichia coli and Pseudomonas aeruginosa, and two Gram-positive bacterial strains, Bacillus subtilis and Staphylococcus aureus. To our delight, most of these compounds exhibited a dramatic increase in inhibitory potency, compared with the control positive drugs. Among them, compound 4s exhibited the most potent inhibitory activity with IC50 values of 5...
November 10, 2016: Chemical Biology & Drug Design
Sijin Wu, Keren Zhang, Hongqiang Qin, Mingshan Niu, Weijie Zhao, Mingliang Ye, Hanfa Zou, Yongliang Yang
Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anti-carcinogenic, antioxidant and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE...
November 8, 2016: Chemical Biology & Drug Design
Elena Cichero, Michele Tonelli
Recent studies have further investigated the trace amine-associated receptor type 2 (TAAR2) pharmacology, revealing its role not only at the olfactory sensory neurons but also at the immune system, being expressed in human leucocytes. In particular, the ability of this receptor to bind the unselective TAAR ligand 3-iodo-thyronamine (T1 AM) was elucidated, making in the meanwhile the discovery of selective compounds a urgent need to derive much more suitable tools for studying TAARs. In this context, we developed our work on TAAR2 applying a structure-based computational protocol, including TAAR2 homology modelling and T1 AM docking studies...
November 8, 2016: Chemical Biology & Drug Design
Behjat Pouramiri, Setareh Moghimi, Mohammad Mahdavi, Hamid Nadri, Alireza Moradi, Esmat Tavakolinejad-Kermani, Loghman Firoozpour, Ali Asadipour, Alireza Foroumadi
A series of novel benzo[d]oxazole derivatives (6a-n) have been synthesized and biologically evaluated as potential inhibitors of acetylcholinesterases (AChE) and butyrylcholinesterase (BChE). The chemical structures of all final compounds were confirmed by spectroscopic methods. In vitro studies showed that most of the synthesized compounds are potent acetylcholinesterase and butyrylcholinesterase inhibitors. Among them, compounds 6a and 6j strongly inhibited AChE and BChE activities with IC50 values of 1.03-1...
November 8, 2016: Chemical Biology & Drug Design
Mohammad Mahdavi, Shima Dianat, Behnaz Khavari, Setareh Moghimi, Mohammad Abdollahi, Maliheh Safavi, Arash Mouradzadegun, Susan Kabodian-Ardestani, Reyhaneh Sabourian, Saeed Emami, Tahmineh Akbarzadeh, Abbas Shafiee, Alireza Foroumadi
Groebke-Blackburn-Bienayme reaction (GBB) has been utilized for the synthesis of new imidazo[1,2-a]pyrimidine derivatives as novel anticancer agents. The cytotoxic activities of compounds were evaluated against human cancer cell lines including MCF-7, T-47D and MDA-MB-231, compared with etoposide as the standard drug. Among the tested compounds, hydroxy- and/or methoxy-phenyl derivatives (6a-c and 6k) with IC50 values of 6.72-14.36 μM were more potent than etoposide against all cell lines. The acridine-orange/ethidium bromide double staining and DNA-fragmentation studies demonstrated that the cytotoxic effect of 3-hydroxy-4-methoxyphenyl derivative 6c is associated with apoptosis in cancer cells...
November 8, 2016: Chemical Biology & Drug Design
Manli Song, Zhide Guo, Mengna Gao, Changrong Shi, Duo Xu, Linyi You, Xiaowei Wu, Xinhui Su, Rongqiang Zhuang, Weimin Pan, Ting Liu, Xianzhong Zhang
Folate receptor is an ideal target for tumor-specific diagnostic and therapeutic. The aim of this study was to synthesize (99m) Tc-labeled folate-polyamidoamine dendrimer modified with 2-hydrazinonicotinic acid ((99m) Tc-HP3 FA) for FR imaging. The (99m) Tc-HP3 FA conjugate was prepared using N-tris-(hydroxymethyl)-methylglycine and trisodium triphenylphosphine-3,3',3″-trisulfonate as coligands. Physicochemical properties, in vitro cell uptake study, and in vivo micro-single-photon emission computed tomography/CT imaging were performed...
November 7, 2016: Chemical Biology & Drug Design
Ehtesham Jameel, Huma Naz, Parvez Khan, Mohd Tarique, Jitendra Kumar, Syed Mumtazuddin, Shahzaib Ahamad, Asimul Islam, Faizan Ahmad, Nasimul Hoda, Md Imtaiyaz Hassan
Calcium/calmodulin-dependent protein kinase IV (CAMKIV) is a multifunctional Ser/Thr kinase, associated with cerebral hypoxia, cancer, and neurodegenerative diseases. Here, we report design, synthesis, and biological evaluation of seven pyrimidine-substituted novel inhibitors of CAMKIV. We successfully synthesized and extensively characterized (ESI-MS, (1) H NMR, and (13) C NMR studies) seven compounds that are showing appreciable binding affinity to the CAMKIV. Molecular docking and fluorescence binding studies revealed that compound 1 is showing very high binding free energy (ΔG = -11...
November 3, 2016: Chemical Biology & Drug Design
Jin Li, Shuying Li, Fengzhong Wang, Fengjiao Xin
The AMP-activated protein kinase (AMPK), a complicated αβγ heterotrimer, can sense cellular energy status and maintain energy homeostasis via switching catabolic and anabolic pathways. AMPK also participates in the regulation of many other life activities, including the cell cycle, cell polarity, autophagy, life span, etc. Therefore, AMPK is widely studied as a potential drug target for treatment of type 2 diabetes (T2D) and some other metabolic diseases, cancers and cardiovascular diseases. Similar to other kinases, the phosphorylation of α-Thr172 in the activation loop by upstream kinases is crucial for the activation of AMPK...
November 3, 2016: Chemical Biology & Drug Design
Panneerselvam Theivendren, Arumugam Subramanian, Indhumathy Murugan, Shrinivas D Joshi, Uttam A More
In this study, drug target was identified using KEGG database and network analysis through Cytoscape software. Designed series of novel benzimidazoles were taken along with reference standard Flibanserin for insilico modeling. The novel 4-(1H-benzo[d]imidazol-2-yl)-N-(substituted phenyl)-4-oxobutanamide (3a-j) analogs were synthesized and evaluated for their antidepressant activity. Reaction of 4-(1H-benzo[d]imidazol-2-yl)-4-oxobutanoic acid (1) with 4-(1H-benzo [d] imidazol-2-yl)-4-oxobutanoyl chloride (2) furnished novel 4-(1H-benzo [d] imidazol-2-yl)-N-(substituted phenyl)-4-oxobutanamide (3a-j)...
October 31, 2016: Chemical Biology & Drug Design
Linkai Mou, Tongwei Cui, Weiguang Liu, Hong Zhang, Zhanxiu Cai, Shaoyong Lu, Guojun Gao
Akt is a serine/threonine protein kinase, a critical mediator of growth factor-induced survival in key cellular pathways. Allosteric signaling between protein intramolecular domains requires long-range communication mediated by hotspots residues, often triggered by ligand binding. Here, based on extensive 3 microsecond explicit solvent molecular dynamics (MD) simulations of Akt1 kinase domain in the unbound (apo) and ATP-competitive inhibitor, GDC-0068-bound states, we propose a molecular mechanism for allosteric regulation of Akt1 kinase phosphorylation by GDC-0068 binding to the ATP-binding site...
October 31, 2016: Chemical Biology & Drug Design
Angelika Drynda, Bożena Obmińska-Mrukowicz, Ewa Zaczyńska, Michał Zimecki, Iwona Kochanowska, Stanisław Ryng, Marcin Mączyński
Isoxazoles are an important class of compounds of potential therapeutic value. The aim of this study was to determine immunotropic effects of 5-amino-3-methyl-4-isoxazolecarboxylic acid hydrazide derivatives on spontaneous and mitogen-induced lymphocyte proliferation in young and old mice, cytokine production by peritoneal cells as well as possible mechanism of action in a model of Jurkat cells. Three month and thirteen month old BALB/c mice were used as donors of the cells from a thymus, a spleen, mesenteric lymph nodes and a peritoneal cavity...
October 25, 2016: Chemical Biology & Drug Design
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