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https://www.readbyqxmd.com/read/28231521/therapeutic-journey-of-2-4-thiazolidinediones-as-a-versatile-scaffold-an-insight-into-structure-activity-relationship
#1
REVIEW
Mohd Javed Naim, Md Jahangir Alam, Shujauddin Ahmad, Farah Nawaz, Neelima Shrivastava, Meeta Sahu, Ozair Alam
Thiazolidinedione is an important heterocyclic ring system, a pharmacophore and a privileged scaffold in medicinal chemistry; is a derivative of thiazolidine ring which came into existence for its role as antihyperglycemic agent and a specific ligand of PPAR's (Peroxisome proliferator activated receptor). Exhaustive research has led to determination of its vast biological profile with wide range of therapeutic applications. This review covers recent pharmacological advancements of thiazolidinedione moiety along with structure activity relationship so as to provide better correlation among different structures and their receptor interactions...
February 20, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28220535/interaction-of-approved-drugs-with-synaptic-vesicle-protein-2a
#2
Azeem Danish, Vigneshwaran Namasivayam, Anke C Schiedel, Christa E Müller
Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [(3) H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM...
February 21, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28220105/acth-receptor-mc2r-specificity-what-do-we-know-about-underlying-molecular-mechanisms
#3
REVIEW
Davids Fridmanis, Ance Roga, Janis Klovins
Coincidentally, the release of this Research Topic in Frontiers in Endocrinology takes place 25 years after the discovery of the adrenocorticotropic hormone receptor (ACTHR) by Mountjoy and colleagues. In subsequent years, following the discovery of other types of mammalian melanocortin receptors (MCRs), ACTHR also became known as melanocortin type 2 receptor (MC2R). At present, five types of MCRs have been reported, all of which share significant sequence similarity at the amino acid level, and all of which specifically bind melanocortins (MCs)-a group of biologically active peptides generated by proteolysis of the proopiomelanocortin precursor...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28218838/design-and-synthesis-of-enantiomerically-pure-decahydroquinoxalines-as-potent-and-selective-%C3%AE%C2%BA-opioid-receptor-agonists-with-anti-inflammatory-activity-in-vivo
#4
Michael Soeberdt, Peter Molenveld, Roy P M Storcken, Renaud Bouzanne des Mazery, Geert Jan Sterk, Reshma Autar, Marjon G Bolster, Clemens Wagner, Sebastianus N H Aerts, Frank R van Holst, Anita Wegert, Giovanni Tangherlini, Bastian Frehland, Dirk Schepmann, Dieter Metze, Tobias Lotts, Ulrich Knie, Kun-Yuan Lin, Tai-Yu Huang, Chih-Ching Lai, Sonja Ständer, Bernhard Wünsch, Christoph Abels
In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [(35)S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor...
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28218273/discovery-of-the-first-dual-inhibitor-of-the-5-lipoxygenase-activating-protein-and-soluble-epoxide-hydrolase-using-pharmacophore-based-virtual-screening
#5
Veronika Temml, Ulrike Garscha, Erik Romp, Gregor Schubert, Jana Gerstmeier, Zsofia Kutil, Barbara Matuszczak, Birgit Waltenberger, Hermann Stuppner, Oliver Werz, Daniela Schuster
Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation...
February 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28217800/x-ray-crystallographic-structure-of-a-teixobactin-analogue-reveals-key-interactions-of-the-teixobactin-pharmacophore
#6
H Yang, D R Du Bois, J W Ziller, J S Nowick
The X-ray crystallographic structure of a truncated teixobactin analogue reveals hydrogen-bonding and hydrophobic interactions and a cavity that binds a chloride anion. Minimum inhibitory concentration (MIC) assays against Gram-positive bacteria correlate the observed structure with antibiotic activity.
February 20, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28215170/derivatives-of-6-nitrobenzimidazole-inhibit-fructose-mediated-protein-glycation-and-intracellular-reactive-oxygen-species-production
#7
Humera Jahan, Muhammad Iqbal Choudhary, Zarbad Shah, Khalid M Khan, Atta-Ur-Rahman
BACKGROUND: Benzimidazoles are important pharmacophores in drug discovery. Several of them are currently used drugs, such as flubendazole, omeprazole, and astemizole for the treatment of anthelmintic, antiulcerative, and antihistaminic diseases, respectively. OBJECTIVES: The aim of the current study was to study the antiglycation activity of nitrobenzimidazole derivatives against fructose-mediated human serum albumin (HSA) glycation. The study was also aimed to investigate effects of newly identified antiglycation inhibitors on AGEs-induced intracellular reactive oxygen species production, and associated impaired proliferation of the hepatocytes...
February 16, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28214076/erratum-to-a-triple-exon-skipping-luciferase-reporter-assay-identifies-a-new-clk-inhibitor-pharmacophore-bioorg-med-chem-lett-27-2017-406-412
#8
Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C Sambucetti, Thomas R Webb
No abstract text is available yet for this article.
February 14, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28212015/discovery-and-preclinical-characterization-of-3-4-4-chlorophenyl-7-fluoroquinoline-3-yl-sulfonyl-benzonitrile-a-novel-non-acetylenic-metabotropic-glutamate-receptor-5-mglur5-negative-allosteric-modulator-for-psychiatric-indications
#9
János Galambos, Attila Bielik, Mikhail Krasavin, Zoltán Orgován, György Domány, Katalin Nógrádi, Gábor Wágner, György T Balogh, Zoltán Béni, János Koti, Zoltán Szakács, Amrita Bobok, Sándor Kolok, Mónika L Miko-Bakk, Mónika Vastag, Katalin Sághy, Judit Laszy, Attila Sándor Halász, Ottilia Balázs, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keserű
Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as potential pharmacotherapy for a number of psychiatric diseases including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore...
February 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28208018/pharmacophore-mapping-of-thienopyrimidine-based-monophosphonate-thp-mp-inhibitors-of-the-human-farnesyl-pyrophosphate-synthase
#10
Jaeok Park, Chun Yuen Leung, Alexios N Matralis, Cyrus M Lacbay, Michail Tsakos, Guillermo Fernandez De Troconiz, Albert M Berghuis, Youla S Tsantrizos
The human farnesyl pyrophosphate synthase (hFPPS), a key regulatory enzyme in the mevalonate pathway, catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate (FPP). FPP plays a crucial role in the post-translational prenylation of small GTPases that perform a plethora of cellular functions. Although hFPPS is a well-established therapeutic target for lytic bone diseases, the currently available bisphosphonate drugs exhibit poor cellular uptake and distribution into non-skeletal tissues. Recent drug discovery efforts have focused primarily on allosteric inhibition of hFPPS and the discovery of non-bisphosphonate drugs for potentially treating non-skeletal diseases...
February 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28205403/functionalized-calix-4-arenes-as-potential-therapeutic-agents
#11
Muhammad Moazzam Naseer, Mukhtiar Ahmed, Shahid Hameed
Calixarenes, composed of phenolic units linked by methylene bridges at the 2,6-positions, represent a versatile class of macrocyclic compounds in supramolecular chemistry that can host small molecules or ions in their well-defined hydrophobic cavities. In recent years, it has been recognized that this class of compounds has the potential to serve as platform for the design of biological active compounds. Therefore, the calixarenes functionalized with different pharmacophoric groups have been synthesized as target structure by many researchers and were further evaluated for their biological activities...
February 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28198152/discovery-of-cdc25a-lead-inhibitors-with-novel-chemotype-by-virtual-screening-application-of-pharmacophore-modeling-based-on-training-set-with-unique-limited-components
#12
Yushu Ge, Qianqian Han, Wenxiu Duan, Jiaqi Zhang, Kai Chen, Jiajia Wan, Yi Liu, Dan Liu
Cdc25 phosphatase has been studied as an attractive target for cancer therapy. Multiple pharmacophore models with unique core features of classic quinone inhibitors and novel inhibitors were used to discover novel lead inhibitor. 21 compounds with qualified physical properties were screened out from Maybridge hitfinderTM database containing 14400 compounds by pharmacophore models. 4 compounds inhibit the Cdc25A activity more than 50% at concentration of 100 μM. Among them, compound KM10389 (N-(2-((furan-2-ylmethyl)thio)ethyl)-2-((4-hydroxy-6-propylpyrimidin-2-yl)thio)acetamide) shows high enzyme inhibition activity with IC₅₀ of 7...
February 14, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28197307/synthesis-and-antitumor-activity-evaluation-of-a-novel-combi-nitrosourea-prodrug-bgcnu
#13
Yameng Wang, Ting Ren, Xinxin Lai, Guohui Sun, Lijiao Zhao, Na Zhang, Rugang Zhong
Chloroethylnitrosoureas (CENUs) are an important type of alkylating agent employed in the clinical treatment of cancer. However, the anticancer efficacy of CENUs is greatly decreased by a DNA repairing enzyme, O(6)-alkylguanine-DNA alkyltransferase (AGT), by preventing the formation of interstrand cross-links (ICLs). In this study, a combi-nitrosourea prodrug, namely, N-(2-chloroethyl)-N'-2-(O(6)-benzyl-9-guanine)ethyl-N-nitrosourea (BGCNU), which possesses an O(6)-benzylguanine (O(6)-BG) derivative and CENU pharmacophores simultaneously, was synthesized and evaluated for its ability to induce ICLs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28193646/simplified-reversed-chloroquines-to-overcome-malaria-resistance-to-quinoline-based-drugs
#14
Bornface Gunsaru, Steven J Burgess, Westin Morrill, Jane X Kelly, Shawheen Shomloo, Martin J Smilkstein, Katherine Liebmann, David H Peyton
Building on our earlier work of attaching a chemosensitizer (reversal agent) to a known drug pharmacophore, we have now expanded the structure-activity relationship study to include simplified versions of the chemosensitizer. The change from two aromatic rings in this head group to a single ring, in fact, does not appear to detrimentally affect the antimalarial activity of the compounds. Data from in vitro heme binding and β-hematin inhibition assays suggest that the single aromatic RCQ compounds retain similar activities against P...
February 13, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28191850/discovery-of-an-inhibitor-of-the-proteasome-subunit-rpn11
#15
Christian Perez, Jing Li, Francesco Parlati, Matthieu Rouffet, Yuyong Ma, Andrew L Mackinnon, Tsui-Fen Chou, Raymond J Deshaies, Seth M Cohen
The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn(2+)-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28186762/synthesis-and-pharmacological-characterization-of-novel-trans-cyclopropylmethyl-linked-bivalent-ligands-that-exhibit-selectivity-and-allosteric-pharmacology-at-the-dopamine-d3-receptor-d3r
#16
Vivek Kumar, Amy E Moritz, Thomas M Keck, Alessandro Bonifazi, Michael P Ellenberger, Christopher D Sibley, R Benjamin Free, Lei Shi, J Robert Lane, David R Sibley, Amy Hauck Newman
The development of bitopic ligands directed toward D2-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D3 receptor (D3R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D3R-selective antagonists SB269,652 (1) and SB277011A (2) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28185719/the-induction-of-oxidative-stress-in-cervix-carcinoma-cells-by-levoglucosenone-derived-4-s-salicyl-derivative-and-1-4-s-thio-disaccharides-part-4
#17
Joanna Sarnik, Anna Czubatka-Bienkowska, Anna Macieja, Roman Bielski, Zbigniew J Witczak, Tomasz Poplawski
(1-4)-S-thiodisaccharides were shown to kill various cancer cell lines, including cervix, lung, mammary-gland and colon by unknown mechanisms. Here we identified two actions of levoglucosenone derived (1-4)-S-thiodisaccharides against cervix cancer cells: induction of oxidative stress and DNA damage. In consequence, (1-4)-S-thiodisaccharides lowered the cellular GSH level and changed the expression profile of genes encoding key proteins involved with oxidative stress response. We also observed that (1-4)-S-thiodisaccharides induced DNA damage and interfered with the thioredoxin (Trx) system...
January 22, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28181424/medicinal-chemisry-profiling-of-monocyclic-1-2-azaborines
#18
Peng Zhao, David O Nettleton, Rajeshri G Karki, Frederic J Zecri, Shih-Yuan Liu
The first examples of biologically active monocyclic 1,2- azaborines have been synthesized and demonstrated to exhibit not only improved in vitro aqueous solubility in comparison to the corresponding carbonaceous analogues, but in the context of a CDK2 inhibitor, also improved biological activity and better in vivo oral bioavailability. This proof-of-concept study establishes the viability of monocyclic 1,2-azaborines as a novel pharmacophore with distinct pharmacological profiles that can help address challenges associated with solubility in drug development research...
February 8, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28178358/substrate-analogous-inhibitors-exert-antimalarial-action-by-targeting-the-plasmodium-lactate-transporter-pffnt-at-nanomolar-scale
#19
André Golldack, Björn Henke, Bärbel Bergmann, Marie Wiechert, Holger Erler, Alexandra Blancke Soares, Tobias Spielmann, Eric Beitz
Resistance against all available antimalarial drugs calls for novel compounds that hit unexploited targets in the parasite. Here, we show that the recently discovered Plasmodium falciparum lactate/proton symporter, PfFNT, is a valid druggable target, and describe a new class of fluoroalkyl vinylogous acids that potently block PfFNT and kill cultured parasites. The original compound, MMV007839, is derived from the malaria box collection of potent antimalarials with unknown targets and contains a unique internal prodrug principle that reversibly switches between a lipophilic transport form and a polar, substrate-analogous active form...
February 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28177238/design-synthesis-and-biological-evaluation-of-mitochondria-targeted-flavone-naphthalimide-polyamine-conjugates-with-antimetastatic-activity
#20
Fujun Dai, Qian Li, Yuxia Wang, Chaochao Ge, Chenyang Feng, Songqiang Xie, Haoying He, Xiaojuan Xu, Chaojie Wang
Approximately 90% of cancer-associated deaths result from disseminated tumors, indicating the ineffectiveness of current therapies and the imperative need of antimetastatic drugs. A novel pharmacophore with flavonoid and naphthalimide moieties was constructed by using a fragment-based drug design and a series of eight flavone-naphthalimide-polyamine conjugates were synthesized. In vitro evaluation revealed that compound 6c with a homospermidine motif displayed better cell selectivity between cancerous and normal liver cells than amonafide did...
February 8, 2017: Journal of Medicinal Chemistry
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