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https://www.readbyqxmd.com/read/28926955/identification-of-novel-bisbenzimidazole-derivatives-as-anticancer-vacuolar-h%C3%A2-%C2%BA-atpase-inhibitors
#1
Renukadevi Patil, Arpita Kulshrestha, Anjali Tikoo, Sara Fleetwood, Gajendra Katara, Bala Kolli, William Seibel, Alice Gilman-Sachs, Shivaputra A Patil, Kenneth D Beaman
The vacuolar (H⁺)-ATPases (V-ATPases) are a family of ATP-driven proton pumps and they have been associated with cancer invasion, metastasis, and drug resistance. Despite the clear involvement of V-ATPases in cancer, the therapeutic use of V-ATPase-targeting small molecules has not reached human clinical trials to date. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. We identified a bisbenzimidazole derivative (V) as an initial hit from a similarity search using four known V-ATPase inhibitors (I-IV)...
September 16, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28925944/interference-of-paraben-compounds-with-estrogen-metabolism-by-inhibition-of-17%C3%AE-hydroxysteroid-dehydrogenases
#2
Roger T Engeli, Simona R Rohrer, Anna Vuorinen, Sonja Herdlinger, Teresa Kaserer, Susanne Leugger, Daniela Schuster, Alex Odermatt
Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating 17β-HSD2. A ligand-based 17β-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17β-HSD1 and 17β-HSD2 activities...
September 19, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28921842/anchorquery-rapid-online-virtual-screening-for-small-molecule-protein-protein-interaction-inhibitors
#3
David R Koes, Alexander Dömling, Carlos J Camacho
AnchorQuery ( http://anchorquery.csb.pitt.edu) is a web application for rational structure-based design of protein-protein interaction (PPI) inhibitors. A specialized variant of pharmacophore search is used to rapidly screen libraries consisting of more than 31 million synthesizable compounds biased by design to preferentially target PPIs. Every library compound is accessible through one-step multi-component reaction (MCR) chemistry and contains an anchor motif that is bioisosteric to an amino acid residue...
September 16, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28918929/vitamin-d-receptor-targeted-treatment-to-prevent-pathological-dedifferentiation-of-pancreatic-%C3%AE-cells-under-hyperglycaemic-stress
#4
A Neelankal John, Z Iqbal, S Colley, G Morahan, M Makishima, F-X Jiang
Dedifferentiation has been identified as one of the causes of β-cell failure resulting in type 2 diabetes (T2D). This study tested whether increasing vitamin D receptor (VDR) expression prevents dedifferentiation of β cells in a high-glucose state in vitro. Culturing a mouse insulinoma cell line (MIN6) in a high-glucose environment decreased VDR expression. However, increased VDR following vitamin D3 (VD3) treatment improved insulin release of early-passage MIN6 and insulin index of db/- (heterozygous) islets to levels seen in normal functional islets...
September 11, 2017: Diabetes & Metabolism
https://www.readbyqxmd.com/read/28917147/combined-in-silico-approaches-for-the-identification-of-novel-inhibitors-of-human-islet-amyloid-polypeptide-hiapp-fibrillation
#5
Palak Patel, Krupali Parmar, Vivek K Vyas, Dhaval Patel, Mili Das
Human islet amyloid polypeptide (hIAPP) is a natively unfolded polypeptide hormone of glucose metabolism, which is co-secreted with insulin by the β-cells of the pancreas. In patients with type 2 diabetes, IAPP forms amyloid fibrils because of diabetes-associated β-cells dysfunction and increasing fibrillation, in turn, lead to failure of secretory function of β-cells. This provides a target for the discovery of small organic molecules against protein aggregation diseases. However, the binding mechanism of these molecules with monomers, oligomers and fibrils to inhibit fibrillation is still an open question...
September 6, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28913661/discovery-of-non-peptidic-small-molecule-inhibitors-of-cyclophilin-d-as-neuroprotective-agents-in-a%C3%AE-induced-mitochondrial-dysfunction
#6
Insun Park, Ashwini M Londhe, Ji Woong Lim, Beoung-Geon Park, Seo Yun Jung, Jae Yeol Lee, Sang Min Lim, Kyoung Tai No, Jiyoun Lee, Ae Nim Pae
Cyclophilin D (CypD) is a mitochondria-specific cyclophilin that is known to play a pivotal role in the formation of the mitochondrial permeability transition pore (mPTP).The formation and opening of the mPTP disrupt mitochondrial homeostasis, cause mitochondrial dysfunction and eventually lead to cell death. Several recent studies have found that CypD promotes the formation of the mPTP upon binding to β amyloid (Aβ) peptides inside brain mitochondria, suggesting that neuronal CypD has a potential to be a promising therapeutic target for Alzheimer's disease (AD)...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28910705/pharmacophore-modeling-virtual-screening-and-molecular-docking-of-atpase-inhibitors-of-hsp70
#7
K Sangeetha, R P Sasikala, K S Meena
Heat shock protein 70 is an effective anticancer target as it influences many signaling pathways. Hence the study investigated the important pharmacophore feature required for ATPase inhibitors of HSP70 by generating a ligand based pharmacophore model followed by virtual based screening and subsequent validation by molecular docking in Discovery studio V4.0. The most extrapolative pharmacophore model (hypotheses 8) consisted of four hydrogen bond acceptors. Further validation by external test set prediction identified 200 hits from Mini Maybridge, Drug Diverse, SCPDB compounds and Phytochemicals...
June 26, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28903337/targeting-the-apoptotic-mcl-1-puma-interface-with-a-dual-acting-compound
#8
Jiyuan Liu, Zhen Tian, Nan Zhou, Xueying Liu, Chenyi Liao, Beilei Lei, Jianing Li, Shengyong Zhang, Hui Chen
Despite intensive efforts in the search for small molecules with anti-cancer activity, it remains challenging to achieve both high effectiveness and safety, since many agents lack the selectivity to only act on cancer cells. The interface of two apoptotic proteins, myeloid cell leukemia-1 (Mcl-1) and p53 upregulated modulator of apoptosis (PUMA), has been recently affirmed as a target for treating cancers, as the disruption of Mcl-1-PUMA binding can reduce cancer cell survival and protect normal cells from apoptosis...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28901854/pharmacophore-comparison-and-development-of-recently-discovered-long-chain-arylpiperazine-and-sulfonamide-based-5-ht7-ligands
#9
Andrea Rague, Kevin Joseph Tidgewell
The serotonin system exerts its effects on the CNS and many peripheral systems. Of the 14 serotonin receptors, the 5-HT7 receptor is the most recently discovered. The 5-HT7 receptor has been shown to be involved in stress reduction, depression, and nociceptive control. Despite the 20 years since the discovery of 5-HT7R, there are still few truly selective ligands. Two of the common scaffolds for 5-HT7R ligands are long chain arylpiperazines (LCAPs) and sulfonamide containing compounds. This review focuses on recently developed (2014-2016) 5-HT7R ligands, their selectivity for the receptor, and suggests possible new pharmacophore models for these ligands...
September 12, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28901664/pharmacophore-based-virtual-screening-molecular-docking-molecular-dynamics-simulation-and-biological-evaluation-for-the-discovery-of-novel-brd4-inhibitors
#10
Guoyi Yan, Manzhou Hou, Jiang Luo, Chunlan Pu, Xueyan Hou, Suke Lan, Rui Li
Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors by using pharmacophore based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules out of twelve hits were found to be active in bioactivity tests...
September 13, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28901263/%C3%AE-aroylketene-dithioacetal-mediated-synthesis-of-e-3-benzo-d-thiazol-2-ylamino-2-1-methyl-1h-indole-3-carbonyl-3-methylthio-acrylonitrile-derivatives-and-their-biological-evaluation
#11
Pravin Bhale, Hemant Vilas Chavan, Sakharam B Dongare, Sagar T Sankpal, Babasaheb P Bandgar
• Background: The blending of two pharmacophores would generate novel molecular templates that are likely to exhibit interesting biological properties. • Objective: A facile, efficient and high yielding synthesis of (E)-3-(benzo[d]thiazol-2-ylamino)-2-(1-methyl-1H-indole-3-carbonyl)-3-(methylthio) acrylonitrile derivatives and evaluation of therapeutic potential. • Method: The synthesis of target molecules has been achieved by reacting 2-aminobenzothiazole and substituted 2-(1-methyl-1H-indole-3-carbonyl)-3,3-bis(methylthio)acrylonitrile in the presence of a catalytic amount of sodium hydride in THF...
September 12, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28900197/structural-insights-into-the-middle-east-respiratory-syndrome-coronavirus-4a-protein-and-its-dsrna-binding-mechanism
#12
Maria Batool, Masaud Shah, Mahesh Chandra Patra, Dhanusha Yesudhas, Sangdun Choi
Middle East respiratory syndrome coronavirus (MERS-CoV) has evolved to navigate through the sophisticated network of a host's immune system. The immune evasion mechanism including type 1 interferon and protein kinase R-mediated antiviral stress responses has been recently attributed to the involvement of MERS-CoV protein 4a (p4a) that masks the viral dsRNA. However, the structural mechanism of how p4a recognizes and establishes contacts with dsRNA is not well explained. In this study, we report a dynamic mechanism deployed by p4a to engage the viral dsRNA and make it unavailable to the host immune system...
September 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899791/toward-a-hierarchical-virtual-screening-and-toxicity-risk-analysis-for-identifying-novel-ca-xii-inhibitors
#13
Elmira Nazarshodeh, Sajjad Gharaghani
Carbonic anhydrase isoform XII (CA XII) is a potential target for cancer treatment. In this study, pharmacophore modeling, hierarchical virtual screening, and toxicity risk analysis were performed for identifying novel CA XII inhibitors. A pharmacophore model of two classes of CA XII inhibitors was generated. The pharmacophore model indicated the important features of inhibitors for the binding with the CA XII. The model was then utilized to screen the ZINC and CoCoCo databases for retrieving potential hit compounds of CA XII...
September 9, 2017: Bio Systems
https://www.readbyqxmd.com/read/28898098/substituent-effects-on-the-coordination-chemistry-of-metal-binding-pharmacophores
#14
Whitney R Craig, Tessa W Baker, Amy R Marts, Daniel T DeGenova, David P Martin, Garrett C Reed, Robert M McCarrick, Michael W Crowder, Seth M Cohen, David L Tierney
A combination of XAS, UV-vis, NMR, and EPR was used to examine the binding of a series of α-hydroxythiones to CoCA. All three appear to bind preferentially in their neutral, protonated forms. Two of the three clearly bind in a monodentate fashion, through the thione sulfur alone. Thiomaltol (TM) appears to show some orientational preference, on the basis of the NMR, while it appears that thiopyromeconic acid (TPMA) retains rotational freedom. In contrast, allothiomaltol (ATM), after initially binding in its neutral form, presumably through the thione sulfur, forms a final complex that is five-coordinate via bidentate coordination of ATM...
September 12, 2017: Inorganic Chemistry
https://www.readbyqxmd.com/read/28892749/virtual-screening-of-b-raf-kinase-inhibitors-a-combination-of-pharmacophore-modelling-molecular-docking-3d-qsar-model-and-binding-free-energy-calculation-studies
#15
Wen Zhang, Kai-Xiong Qiu, Fang Yu, Xiao-Guang Xie, Shu-Qun Zhang, Ya-Juan Chen, Hui-Ding Xie
B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔGbind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines...
August 31, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28891868/a-bivalent-ligand-that-activates-mu-opioid-receptor-and-antagonizes-mglur5-receptor-reduces-neuropathic-pain-in-mice
#16
Cristina D Peterson, Kelley F Kitto, Eyup Akgün, Mary M Lunzer, Maureen S Riedl, Lucy Vulchanova, George L Wilcox, Philip S Portoghese, Carolyn A Fairbanks
The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in spinal cord. MMG22, a bivalent ligand containing two pharmacophores separated by 22 atoms that simultaneously activates MOR and antagonizes mGluR5 has been shown to produce potent reversal of tactile hypersensitivity in rodent models of LPS- and bone-cancer-induced chronic pain. The present study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin...
September 1, 2017: Pain
https://www.readbyqxmd.com/read/28888144/previously-undescribed-fridooleanenes-and-oxygenated-labdanes-from-the-brown-seaweed-sargassum-wightii-and-their-protein-tyrosine-phosphatase-1b-inhibitory-activity
#17
Anusree Maneesh, Kajal Chakraborty
Previously undescribed fridooleanene triterpenoids 2α-hydroxy-(28,29)-frido-olean-12(13), 21(22)-dien-20-propyl-21-hex-4'(Z)-enoate, 2α-hydroxy-(28,29)-frido-olean-12(13), 21(22)-dien-20-prop-2(E)-en-21-butanoate and oxygenated labdane diterpenoids 2α-hydroxy-8(17), (12E), 14-labdatriene, 3β, 6β, 13α-tri hydroxy 8(17), 12E, 14-labdatriene were purified from the ethyl acetate-methanol and dichloromethane fractions of the air-dried thalli of Sargassum wightii (Sargassaceae), a brown seaweed collected from the Gulf-of-Mannar of Penninsular India...
September 6, 2017: Phytochemistry
https://www.readbyqxmd.com/read/28888096/exploration-of-thioxothiazolidinone-sulfonate-conjugates-as-a-new-class-of-aldehyde-aldose-reductase-inhibitors-a-synthetic-and-computational-investigation
#18
Hina Andleeb, Yildiz Tehseen, Farrukh Jabeen, Imtiaz Khan, Jamshed Iqbal, Shahid Hameed
In the present study, the pharmacophore integration methodology provided an efficient access to a new library of thioxothiazolidinone-sulfonate conjugates (8a-r) from easily available synthetic precursors. The approach was excellently high yielding with flexible structural sites for chemical modifications. The designed hybrid scaffolds were assessed for aldehyde/aldose reductase inhibition activities. The results for the in vitro bioassays were promising with the identification of compound 8e as the lead and selective candidate for ALR2 inhibition with an IC50 value of 0...
August 31, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28885019/sulfonium-as-a-surrogate-for-ammonium-a-new-%C3%AE-7-nicotinic-acetylcholine-receptor-partial-agonist-with-desensitizing-activity
#19
Marta Quadri, Clare Stokes, Alican Gulsevin, Ashley C J Felts, Khalil A Abboud, Roger L Papke, Nicole A Horenstein
Weak partial agonists that promote a desensitized state of the α7 nicotinic acetylcholine receptor (nAChR) have been associated with anti-inflammatory effects. Exemplar compounds feature a tertiary or quaternary ammonium group. We report the synthesis, structure, and electrophysiological evaluation of 1-ethyl-4-phenylthiomorpholin-1-ium triflate, a weak partial agonist with a sulfonium isostere of the ammonium pharmacophore. These results offer new insights in understanding nAChR-ligand interactions and provide a new chemical space to target the α7 nAChR...
September 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28885004/gold-catalyzed-solid-phase-synthesis-of-3-4-dihydropyrazin-2-1h-ones-relevant-pharmacophores-and-peptide-backbone-constraints
#20
Adam Přibylka, Viktor Krchňák
Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C-N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4-dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory...
September 12, 2017: ACS Combinatorial Science
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