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Sangh Partap, Md Jawaid Akhtar, Mohammed Shahar Yar, Mohd Zaheen Hassan, Anees Ahmad Siddiqui
A series of new hybrid benzothiazole containing pyridazinones derivatives were designed and synthesized fulfilling all the pharmacophoric requirements essential for the anticonvulsant activity. In-silico and in vitro studies revealed that some of these hybrid derivatives demonstrated admirable GABA AT inhibitory activity. An attempt has also been made to validate the results of in vitro GABA AT inhibition of the most potent compound SPS-5F (IC50 9.10 μM) through in vivo anticonvulsant screening. Compound SPS-5F administration significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme...
January 3, 2018: Bioorganic Chemistry
Robert Schulz, Amira Atef, Daniel Becker, Franziska Gottschalk, Carolin Tauber, Stefan Wagner, Christoph Arkona, Atef A Abdel-Hafez, Hassan H Farag, Jörg Rademann, Gerhard Wolber
Lead structure discovery mainly focuses on the identification of noncovalently binding ligands. Covalent linkage, however, is an essential binding mechanism for a multitude of successfully marketed drugs although discovered by serendipity in most cases. We present a concept for the design of fragments covalently binding to proteases. Covalent linkage enables fragment binding unrelated to affinity to shallow protein binding sites and at the same time allows differentiated targeted hit verification and binding location verification through mass spectrometry...
January 12, 2018: Journal of Medicinal Chemistry
Christopher J Draper-Joyce, Mayako Michino, Ravi Kumar Verma, Carmen Klein Herenbrink, Jeremy Shonberg, Anitha Kopinathan, Peter J Scammells, Ben Capuano, David M Thal, Jonathan A Javitch, Arthur Christopoulos, Lei Shi, J Robert Lane
SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity...
January 8, 2018: Biochemical Pharmacology
Preeti Pandey, Vijay Verma, Suman Kumar Dhar, Samudrala Gourinath
The characteristic of interaction with various enzymes and processivity-promoting nature during DNA replication makes β-clamp an important drug target. Helicobacter pylori (H. pylori) have several unique features in DNA replication machinery that makes it different from other microorganisms. To find out whether difference in DNA replication proteins behavior accounts for any difference in drug response when compared to E. coli, in the present study, we have tested E. coli β-clamp inhibitor molecules against H...
January 11, 2018: Antibiotics
Parthiban Marimuthu, Yong-Jin Lee, Byung-Hoon Kim, Seong S Seo
Organophosphate compounds (OPC) have become the primary choice as insecticides and is widely used across the world. Additionally, OPCs were also commonly used as a chemical warfare agent that triggers a great challenge to public safety. Exposure of OPCs to human causes immediate excitation of cholinergic neurotransmission through transient elevation of synaptic acetylcholine (ACh) levels and accumulations. Likewise, prolonged exposure of OPCs can affect the processes in immune response, carbohydrate metabolism, cardiovascular toxicity and several others...
January 11, 2018: Journal of Biomolecular Structure & Dynamics
Xu Zhang, Liansheng Qiao, Yankun Chen, Bowen Zhao, Yu Gu, Xiaoqian Huo, Yanling Zhang, Gongyu Li
The metabotropic glutamate receptors (mGluRs) are known as both synaptic receptors and taste receptors. This feature is highly similar to the Property and Flavor theory of Traditional Chinese medicine (TCM), which has the pharmacological effect and flavor. In this study, six ligand based pharmacophore (LBP) models, seven homology modeling models, and fourteen molecular docking models of mGluRs were built based on orthosteric and allosteric sites to screening potential compounds from Traditional Chinese Medicine Database (TCMD)...
January 10, 2018: International Journal of Molecular Sciences
Corey J Brumsted, Evan L Carpenter, Arup K Indra, Taifo Mahmud
Pactamycin is a structurally unique aminocyclitol antibiotic with broad-spectrum cell growth inhibitory activity. To explore the bountiful activity of the aminocyclitol core of pactamycin, an efficient, modular, and asymmetric synthesis of aminocyclopentitols resembling the pactamycin pharmacophore has been developed employing a SmI2-mediated imino-pinacol coupling strategy. Two of the compounds exhibited antitumor activity against A375 melanoma cells.
January 10, 2018: Organic Letters
Jian Liu, Chengbo Qian, Yehua Zhu, Jianguo Cai, Yufang He, Jie Li, Tianlin Wang, Haohao Zhu, Zhi Li, Wei Li, Lihong Hu
Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven't been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro...
December 29, 2017: Bioorganic & Medicinal Chemistry
Wenlin Xie, Yiqiang Wu, Jingai Zhang, Qihong Mei, Yahan Zhang, Ning Zhu, Renzhi Liu, Huilin Zhang
A hybrid pharmacophore approach was adopted to design and synthesize new series of pyridone-thiazole hybrid compounds. The structures of the compounds were established by IR, 1H NMR, 13C NMR, and HRMS. All the newly prepared compounds (3a-3m) were in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely Colon cancer (HCT-116), gastric carcinoma (MGC803) and hepatocellular cancer (Huh7). Bioassay results demonstrated that most of the tested compounds showed potent anti-tumor activities against various cancer cells in vitro, and some compounds exhibited stronger effects than positive control 5-Fluorouracil (5-FU)...
December 15, 2017: European Journal of Medicinal Chemistry
Miao Yu, Qiong Gu, Jun Xu
PI3Kα is a promising drug target for cancer chemotherapy. In this paper, we report a strategy of combing ligand-based and structure-based virtual screening to identify new PI3Kα inhibitors. First, naïve Bayesian (NB) learning models and a 3D-QSAR pharmacophore model were built based upon known PI3Kα inhibitors. Then, the SPECS library was screened by the best NB model. This resulted in virtual hits, which were validated by matching the structures against the pharmacophore models. The pharmacophore matched hits were then docked into PI3Kα crystal structures to form ligand-receptor complexes, which are further validated by the Glide-XP program to result in structural validated hits...
January 6, 2018: Journal of Computer-aided Molecular Design
Yue Zhou, Na Zhang, Xiaoqian Qi, Shan Tang, Guohui Sun, Lijiao Zhao, Rugang Zhong, Yongzhen Peng
Protein kinase is a novel therapeutic target for human diseases. The off-target and side effects of ATP-competitive inhibitors preclude them from the clinically relevant drugs. The compounds targeting the druggable allosteric sites outside the highly conversed ATP binding pocket have been identified as promising alternatives to overcome current barriers of ATP-competitive inhibitors. By simultaneously interacting with the αD region (new allosteric site) and sub-ATP binding pocket, the attractive compound CAM4066 was named as allosteric inhibitor of CK2α...
January 1, 2018: International Journal of Molecular Sciences
Nikhil Pathak, Mei-Ling Lai, Wen-Yu Chen, Betty-Wu Hsieh, Guann-Yi Yu, Jinn-Moon Yang
BACKGROUND: Viruses of the flaviviridae family are responsible for some of the major infectious viral diseases around the world and there is an urgent need for drug development for these diseases. Most of the virtual screening methods in flaviviral drug discovery suffer from a low hit rate, strain-specific efficacy differences, and susceptibility to resistance. It is because they often fail to capture the key pharmacological features of the target active site critical for protein function inhibition...
December 28, 2017: BMC Bioinformatics
Carlos Coriano, Fabao Liu, Chelsie Sievers, Muxuan Liang, Yidan Wang, Yoongho Lim, Menggang Yu, Wei Xu
The biological effects of estrogens are transduced by two estrogen receptors (ERs), ERα and ERβ, which function in dimer forms. The ERα/α homodimer promotes and the ERβ/β inhibits estrogen dependent growth of mammary epithelial cells, the functions of ERα/β heterodimers remain elusive. Using compounds that promote ERα/β heterodimerization, we have shown that ERα/β heterodimers appeared to inhibit tumor cell growth and migration in vitro. Further dissection of ERα/β heterodimer functions was hampered by the lack of ERα/β heterodimer specific ligands...
January 2, 2018: Molecular Pharmacology
Talambedu Usha, Dhivya Shanmugarajan, Arvind Kumar Goyal, Chinaga Suresh Kumar, Sushil Kumar Middha
Computer aided drug designing (CADD) has gained a wide popularity among biologists and chemists as a part of interdisciplinary drug discovery approach. It plays a vital role in the discovery, design and analysis of drugs in pharmaceutical industry. It is extensively used to reduce cost, time and speed up the early stage development of biologically new active molecules. In the current review we presented a brief review of CADD, merits and demerits, DNA, protein and enzyme as targets, types of CADD: Structure based drug designing (SBDD), ligand based drug designing (LBDD), Pharmacophore based drug designing (PBDD) and fragment based drug designing (FBDD), theory behind the types of CADD and their applications...
January 1, 2018: Current Topics in Medicinal Chemistry
Sivakumar Prasanth Kumar, Prakash C Jha
Numerous caspase-3 drug discovery projects were found to have relied on single receptor as the template to recognize most promising small molecule candidates using docking approach. Alternatively, some researchers were contingent upon ligand-based alignment to build up an empirical relationship between ligand functional groups and caspase-3 inhibitory activity quantitatively. To connect both caspase-3 receptor details and its inhibitors chemical functionalities, we developed multi-pharmacophore model based on flexible (conformations unrestricted or flexible during pharmacophore mapping), dock (conformations obtained using FlexX docking method) and crystal (extracted from multiple caspase-3-ligand complexes from PDB repository) conformations of query ligands...
January 1, 2018: Combinatorial Chemistry & High Throughput Screening
Radhika Ramachandran, Shanmughavel Piramanyagam
The C-X-C chemokine receptor type 4 receptor CXCR4 which acts as a co-receptor for human immunodeficiency virus-1, expressed in the later stages of infection is considered as an attractive and new target for drug design. Microbicides acting as co-receptor blockers are highly significant as these drugs block HIV lifecycle at early stage itself. The urgent need for a safe and effective microbicide urges to explore new CXCR4 antagonists which could be developed as microbicides. The pharmacophore based 3D-QSAR models and docking models were developed using PHASE and GLIDE modules of Schrodinger software...
September 2017: Virusdisease
Ghandoura Moussa, Rana Alaaeddine, Lynn M Alaeddine, Rasha Nassra, Ahmed S F Belal, Azza Ismail, Ahmed F El-Yazbi, Yasser S Abdel-Ghany, Aly Hazzaa
Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC50 (μM) 0.18, 0.19, 0.11, 0.16 and 0...
December 18, 2017: European Journal of Medicinal Chemistry
Mohammad Fawad Ansari, Danish Idrees, Md Imtaiyaz Hassan, Kamal Ahmad, Fernando Avecilla, Amir Azam
In order to obtain novel Human carbonic anhydrase IX (CAIX) inhibitors, a series of pyridine-thiazolidinone derivatives was synthesized and characterized by various spectroscopic techniques. The binding affinity of the compounds was measured by fluorescence binding studies and enzyme inhibition activity using esterase assay of CAIX. It was observed that compound 8 and 11 significantly inhibit the CAIX activity with the IC50 value, 1.61 μM and 1.84 μM, respectively. The binding-affinity of compound 8 and 11 for CAIX was significantly high with their KD values 11...
December 15, 2017: European Journal of Medicinal Chemistry
Zhaoping Pan, Yujuan Chen, Jingyan Liu, Qinglin Jiang, Shengyong Yang, Li Guo, Gu He
Both PLK1 and EEF2K are serine⁄threonine kinases that play important roles in the proliferation and programmed cell death of various types of cancer. They are highly expressed in breast cancer tissues. Based on the multiple-complexes generated pharmacophore models of PLK1 and homology models of EEF2K, the integrated virtual screening is performed to discover novel PLK1/EEF2K dual inhibitors. The top ten hit compounds are selected and tested in vitro, and five of them display PLK1 and EEF2K inhibition in vitro...
December 14, 2017: European Journal of Medicinal Chemistry
Jingying Qiu, Qineng Gong, Jian Gao, Wang Chen, Yinpeng Zhang, Xiaoke Gu, Daoquan Tang
As an ongoing search for potent non-nucleoside anti-HBV agents with novel structures, we described a series of phenyl propionamide derivatives (3a-b, 4a-e, 7a-g, 8a-h and 9a-b) by pharmacophore fusion strategy in the present work. All the compounds exhibited an anti-HBV activity to some extent. Among them, compounds 8d and 9b displayed most potent anti-HBV activity with IC50 values on HBV DNA replication of 0.46 and 0.14 μM, respectively. And the selective index values of 8d and 9b were more than 217.39 and 153...
December 16, 2017: European Journal of Medicinal Chemistry
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