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https://www.readbyqxmd.com/read/28636873/mimicking-natural-phytohormones-26-hydroxycholestan-22-one-derivatives-as-plant-growth-promoters
#1
Reyna Zeferino-Diaz, J Ciciolil Hilario-Martinez, Maricela Rodriguez-Acosta, Alan Carrasco-Carballo, Maria Guadalupe Hernandez-Linares, Jesus Sandoval-Ramirez, Maria A Fernandez-Herrera
26-Hydroxycholestan-22-one derivatives with oxygenated functions in the rings A and/or B were successfully synthesized from diosgenin. After the modifications of rings A and B, the spiroketal side chain was selectively opened through a Lewis acid mediated acetolysis to afford the cholestane derivatives. These compounds incorporate pharmacophores, which mimic the activity of natural phytohormones and show high growth promoting activity in Mexican rice cultivars using the rice lamina inclination test.
June 18, 2017: Steroids
https://www.readbyqxmd.com/read/28636128/phosphonium-salts-as-pseudohalides-regioselective-ni-catalyzed-cross-coupling-of-complex-pyridines-and-diazines
#2
Andrew McNally, Xuan Zhang
Heterobiaryls are important pharmacophores that are challenging to prepare by traditional cross-coupling methods. An alternative approach is presented where pyridines and diazines are converted to heteroaryl phosphonium salts and coupled with arylboronic acids. Nickel catalysts are unique for selective heteroaryl transfer, and the reaction has a broad substrate scope that includes complex pharmaceuticals. Phosphonium ions also display orthogonal reactivity in cross-couplings compared to halides enabling chemoselective palladium and nickel-catalyzed coupling sequences...
June 21, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28635653/virtual-screening-against-phosphoglycerate-kinase-1-in-quest-of-novel-apoptosis-inhibitors
#3
Jie Xia, Bo Feng, Qianhang Shao, Yuhe Yuan, Xiang Simon Wang, Naihong Chen, Song Wu
Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28635627/molecular-quantum-similarity-chemical-reactivity-and-database-screening-of-3d-pharmacophores-of-the-protein-kinases-a-b-and-g-from-mycobacterium-tuberculosis
#4
Alejandro Morales-Bayuelo
Mycobacterium tuberculosis remains one of the world's most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these compounds, with anti-tuberculosis activity...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28634338/coumarin-benzimidazole-hybrids-as-a-potent-antimicrobial-agent-synthesis-and-biological-elevation
#5
L Ravithej Singh, Srinivasa Rao Avula, Sneha Raj, Akanksha Srivastava, Gopala Reddy Palnati, C K M Tripathi, Mukesh Pasupuleti, Koneni V Sashidhara
Molecular hybridization approach is an emerging tool in drug discovery for designing new pharmacophores with biological activity. A novel, new series of coumarin-benzimidazole hybrids were designed, synthesized and evaluated for their broad spectrum antimicrobial activity. Among all the synthesized molecules, compound (E)-3-(2-1H-benzo[d]imidazol-1-yl)-1-((4-chlorobenzyl)oxy)imino)ethyl)-2H-chromen-2-one showed the most promising broad spectrum antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris...
June 21, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28634039/synthesis-and-biological-activity-of-peptide-proline-boronic-acids-as-proteasome-inhibitors
#6
Liqiang Han, Yanzhao Wen, Ridong Li, Bo Xu, Zemei Ge, Xin Wang, Tieming Cheng, Jingrong Cui, Runtao Li
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits...
June 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28632406/tailored-pharmacophore-model-to-enhance-virtual-screening-and-drug-discovery-a-case-study-on-the-identification-of-potential-inhibitors-against-drug-resistant-mycobacterium-tuberculosis-3r-hydroxyacyl-acp-dehydratases
#7
Kgothatso E Machaba, Ndumiso N Mhlongo, Yussif M Dokurugu, Mahmoud Es Soliman
AIM: Virtual screening (VS) is powerful tool in discovering molecular inhibitors that are most likely to bind to drug targets of interest. Herein, we introduce a novel VS approach, so-called 'tailored-pharmacophore', in order to explore inhibitors that overcome drug resistance. Methodology & results: The emergence and spread of drug resistance strains of tuberculosis is one of the most critical issues in healthcare. A tailored-pharmacophore approach was found promising to identify in silico predicted hit with better binding affinities in case of the resistance mutations in MtbHadAB as compared with thiacetazone, a prodrug used in the clinical treatment of tuberculosis...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28632381/molecular-modeling-of-the-interactions-between-carborane-containing-analogs-of-indomethacin-and-cyclooxygenase-2
#8
Menyhárt-Botond Sárosi, Wilma Neumann, Terry P Lybrand, Evamarie Hey-Hawkins
Molecular modeling studies were performed in order to gain insight into the binding mode and interaction of carborane-containing derivatives of indomethacin methyl ester with the cyclooxygenase 2 (COX 2) isoform, and to assess the predictive capability of the computational tools available for studying carboranes, a unique class of pharmacophores. Docking simulations were able to identify the correct binding mode and reproduced the experimental binding affinity trends with encouraging quality. Nevertheless, the docking results needed to be verified through extensive and resource intensive quantum chemical calculations, and the interpretation of the theoretical results would not have been straightforward without the supporting experimental data...
June 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28628824/structure-activity-relationship-investigation-for-benzonaphthyridinone-derivatives-as-novel-potent-bruton-s-tyrosine-kinase-btk-irreversible-inhibitors
#9
Beilei Wang, Yuanxin Deng, Yongfei Chen, Kailin Yu, Aoli Wang, Qianmao Liang, Wei Wang, Cheng Chen, Hong Wu, Chen Hu, Weili Miao, Wooyoung Hur, Wenchao Wang, Zhenquan Hu, Ellen L Weisberg, Jinhua Wang, Tao Ren, Yinsheng Wang, Nathanael S Gray, Qingsong Liu, Jing Liu
Through a structure-based drug design approach, a tricyclic benzonaphthyridinone pharmacophore was used as a starting point for carrying out detailed medicinal structure-activity relationhip (SAR) studies geared toward characterization of a panel of proposed BTK inhibitors, including 6 (QL-X-138), 7 (BMX-IN-1) and 8 (QL47). These studies led to the discovery of the novel potent irreversible BTK inhibitor, compound 18 (CHMFL-BTK-11). Kinetic analysis of compound 18 revealed an irreversible binding efficacy (kinact/Ki) of 0...
June 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28628649/insights-into-the-binding-mode-of-mek-type-iii-inhibitors-a-step-towards-discovering-and-designing-allosteric-kinase-inhibitors-across-the-human-kinome
#10
Zheng Zhao, Lei Xie, Philip E Bourne
Protein kinases are critical drug targets for treating a large variety of human diseases. Type-III kinase inhibitors have attracted increasing attention as highly selective therapeutics. Thus, understanding the binding mechanism of existing type-III kinase inhibitors provides useful insights into designing new type-III kinase inhibitors. In this work, we have systematically studied the binding mode of MEK-targeted type-III inhibitors using structural systems pharmacology and molecular dynamics simulation. Our studies provide detailed sequence, structure, interaction-fingerprint, pharmacophore and binding-site information on the binding characteristics of MEK type-III kinase inhibitors...
2017: PloS One
https://www.readbyqxmd.com/read/28627371/structure-activity-relationship-study-of-tetrapeptide-inhibitors-of-the-vascular-endothelial-growth-factor-a-binding-to-neuropilin-1
#11
Dagmara Tymecka, Piotr F J Lipiński, Bartłomiej Fedorczyk, Anna Puszko, Beata Wileńska, Gerard Y Perret, Aleksandra Misicka
Neuropilin-1 is considered as one of the key receptors responsible for signaling pathways involved in pathological angiogenesis necessary for tumor progression, therefore targeting of VEGF165 binding to NRP-1 could be a relevant strategy for antiangiogenic treatment. It was shown before that the VEGF165/NRP-1 interaction can be inhibited by short tetrapeptides with K/RXXR sequence. Here, we present a structure-activity relationship study of the systematic optimization of amino acid residues in positions 1-3 in the above tetrapeptides...
June 13, 2017: Peptides
https://www.readbyqxmd.com/read/28626481/quantum-mechanical-molecular-mechanical-and-docking-study-of-the-novel-analogues-based-on-hybridization-of-common-pharmacophores-as-potential-anti-breast-cancer-agents
#12
Parvin Asadi, Ghadamali Khodarahmi, Hossein Farrokhpour, Farshid Hassanzadeh, Lotfollah Saghaei
In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran-imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method...
June 2017: Research in Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28623487/multiple-receptor-ligand-based-pharmacophore-modeling-and-molecular-docking-to-screen-the-selective-inhibitors-of-matrix-metalloproteinase-9-from-natural-products
#13
Qi Gao, Yijun Wang, Jiaying Hou, Qizheng Yao, Ji Zhang
Matrix metalloproteinase-9 (MMP-9) is an attractive target for cancer therapy. In this study, the pharmacophore model of MMP-9 inhibitors is built based on the experimental binding structures of multiple receptor-ligand complexes. It is found that the pharmacophore model consists of six chemical features, including two hydrogen bond acceptors, one hydrogen bond donor, one ring aromatic regions, and two hydrophobic (HY) features. Among them, the two HY features are especially important because they can enter the S1' pocket of MMP-9 which determines the selectivity of MMP-9 inhibitors...
June 16, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28622907/synthesis-biological-evaluation-and-molecular-modeling-of-imidazo-1-2-a-pyridine-derivatives-as-potent-antitubulin-agents
#14
Jin Liu, Daiying Zuo, Tongfei Jing, Ming Guo, Lingyun Xing, Wenyu Zhang, Jianwen Zhao, Jiwei Shen, Ping Gong, Dajun Zhang, Xin Zhai
Two series of novel 5,7-diarylimidazo[1,2-a]pyridine-8-carbonitrile derivatives (3a-3q and 7a-7n) were designed by modification of CA-4 pharmacophore to develop colchicine targeted antitubulin agents. All compounds were efficiently synthesized and evaluated for their cytotoxicity against five selected cancer cell lines (HT-29, H460, A549, MKN-45 and SMMC-7721) which got an insight in structure and activity relationships (SARs). Several molecules (7e, 7f, 7h-7j and 7m) were disclosed to exhibit promising antiproliferative activity with IC50 values in double-digit nanomolar degree...
May 30, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28621938/inhibition-of-proliferation-of-vascular-smooth-muscle-cells-by-cucurbitanes-from-momordica-charantia
#15
Nguyen Quoc Tuan, Do-Hyung Lee, Joonseok Oh, Chung Sub Kim, Kyung-Sun Heo, Chang-Seon Myung, MinKyun Na
The cucurbitaceous plant Momordica charantia L., named "bitter melon", inhabits Asia, Africa, and South America and has been used as a traditional medicine. The atypical proliferation of vascular smooth muscle cells (VSMCs) plays an important role in triggering the pathogenesis of cardiovascular diseases. Platelet-derived growth factor (PDGF) is regarded as the most powerful growth factor in promoting the intimal accumulation of VSMCs. The current study features the identification of six new cucurbitane-type triterpenoids (1-6) from the fruits of M...
June 16, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28620761/medicinal-chemistry-of-%C3%AF-1-receptor-ligands-pharmacophore-models-synthesis-structure-affinity-relationships-and-pharmacological-applications
#16
Frauke Weber, Bernhard Wünsch
In the first part of this chapter, we summarize the various pharmacophore models for σ1 receptor ligands. Common to all of them is a basic amine flanked by two hydrophobic regions, representing the pharmacophoric elements. The development of computer-based models like the 3D homology model is described as well as the first crystal structure of the σ1 receptor. The second part focuses on the synthesis and biological properties of different σ1 receptor ligands, identified as 1-9. Monocyclic piperazines 1 and bicyclic piperazines 2 and 3 were developed as cytotoxic compounds, thus the IC50 values of cell growth and survival inhibition studies are given for all derivatives...
June 16, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28619751/synthesis-and-profiling-of-a-novel-potent-selective-inhibitor-of-chk1-kinase-possessing-unusual-n-trifluoromethylpyrazole-pharmacophore-resistant-to-metabolic-n-dealkylation
#17
Pounami Samadder, Tereza Suchanková, Ondrej Hylse, Prashant Khirsariya, Fedor Nikulenkov, Stanislav Drápela, Nicol Straková, Petr Vaňhara, Kateřina Vašíčková, Hana Kolářová, Lucia Binó, Miroslava Bittová, Petra Ovesná, Peter Kollar, Radek Fedr, Milan Ešner, Josef Jaroš, Aleš Hampl, Lumír Krejčí, Kamil Paruch, Karel Soucek
Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G2/M checkpoint in the presence of replication stress inflicted by DNA damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity and reduced toxicity of chemotherapy...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28619619/flavin-catalyzed-redox-tailoring-reactions-in-natural-product-biosynthesis
#18
REVIEW
Robin Teufel
Natural products are distinct and often highly complex organic molecules that constitute not only an important drug source, but have also pushed the field of organic chemistry by providing intricate targets for total synthesis. How the astonishing structural diversity of natural products is enzymatically generated in biosynthetic pathways remains a challenging research area, which requires detailed and sophisticated approaches to elucidate the underlying catalytic mechanisms. Commonly, the diversification of precursor molecules into distinct natural products relies on the action of pathway-specific tailoring enzymes that catalyze, e...
June 12, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28618987/synthesis-of-new-thiazolyl-coupled-pyrazoles-bearing-2-4-thiazolidinedionyl-pharmacophore-and-their-anti-inflammatory-and-antibacterial-evaluation
#19
Lalit Khillare, Manisha Bhosle, Mahendra Bhalerao, Kiran Kharat, Ramrao Mane
BACKGROUND: 2, 4-Thiazolidinedione (TZD), pyrazole and thiazole heterocyclic rings exhibit wide range of pharmacological activities. Medicinal chemists use these heterocyclic moieties as scaffolds in drug designing and discovery. The existing medicaments, celecoxib and meloxicam, used for treating inflammation and pain are having, pyrazole and thiazole, respectively as a key scaffolds. Pyrazoles coupled with 2, 4-thiazolidinediones may display enhanced anti inflammatory activity. With this hope the title work was carried...
June 16, 2017: Anti-inflammatory & Anti-allergy Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28617811/genetic-structural-and-chemical-insights-into-the-dual-function-of-grasp55-in-germ-cell-golgi-remodeling-and-jam-c-polarized-localization-during-spermatogenesis
#20
Amandine Cartier-Michaud, Anne-Laure Bailly, Stéphane Betzi, Xiaoli Shi, Jean-Claude Lissitzky, Ana Zarubica, Arnauld Sergé, Philippe Roche, Adrien Lugari, Véronique Hamon, Florence Bardin, Carine Derviaux, Frédérique Lembo, Stéphane Audebert, Sylvie Marchetto, Bénédicte Durand, Jean-Paul Borg, Ning Shi, Xavier Morelli, Michel Aurrand-Lions
Spermatogenesis is a dynamic process that is regulated by adhesive interactions between germ and Sertoli cells. Germ cells express the Junctional Adhesion Molecule-C (JAM-C, encoded by Jam3), which localizes to germ/Sertoli cell contacts. JAM-C is involved in germ cell polarity and acrosome formation. Using a proteomic approach, we demonstrated that JAM-C interacted with the Golgi reassembly stacking protein of 55 kDa (GRASP55, encoded by Gorasp2) in developing germ cells. Generation and study of Gorasp2-/- mice revealed that knock-out mice suffered from spermatogenesis defects...
June 2017: PLoS Genetics
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