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John C Widen, Aaron M Kempema, Jordan W Baur, Hannah M Skopec, Jacob T Edwards, Tenley J Brown, Dennis A Brown, Frederick A Meece, Daniel A Harki
Helenalin is a pseudoguaianolide natural product that targets Cys38 within the DNA binding domain of NF-κB transcription factor p65 (RelA). Helenalin contains two Michael acceptors that covalently modify cysteines: a α-methylene-γ-butyrolactone and a cyclopentenone. We recently reported two simplified helenalin analogues that mimic the biological activity of helenalin and contain both electrophilic moieties. To determine the individual contributions of the Michael acceptors toward NF-κB inhibition, we synthesized a small library of helenalin-based analogues containing various combinations of α-methylene-γ-butyrolactones and cyclopentenones...
January 19, 2018: ChemMedChem
Jussara Amato, Alessia Pagano, Domenica Capasso, Sonia Di Gaetano, Mariateresa Giustiniano, Ettore Novellino, Antonio Randazzo, Bruno Pagano
Targeting of G-quadruplex-forming DNA in BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein represents an attractive opportunity in cancer treatment. So far, efforts made in the discovery of molecules able to target BCL2 G-quadruplex mainly succeeded in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity...
January 18, 2018: ChemMedChem
Albert J Kooistra, Marton Vass, Ross McGuire, Rob Leurs, Iwan Jp de Esch, Gerrit Vriend, Stefan Verhoeven, Chris de Graaf
eScience technologies are needed to process the information available in many heterogeneous types of protein-ligand interaction data and to capture these data into models that enable the design of efficacious and safe medicines. Here we present scientific KNIME tools and workflows that enable the integration of chemical, pharmacological, and structural information for: i) structure-based bioactivity data mapping, ii) structure-based identification of scaffold replacement strategies for ligand design, iii) ligand-based target prediction, iv) protein sequence-based binding site identification and ligand repurposing, and v) structure-based pharmacophore comparison for ligand repurposing across protein families...
January 16, 2018: ChemMedChem
Xiaomin Jia, Zhiyuan Yang, Yujun Wang, Ya Chen, Haitao Yuan, Heyin Chen, Xiaoxiang Xu, Xueqing Gao, Zuozhong Liang, Yu Sun, Jian-Rong Li, Haoquan Zheng, Rui Cao
Metal-organic frameworks (MOFs), a new type of porous crystalline materials, have great potential in biomedical applications, such as drug delivery. However, the efficacy of drug delivery is limited by the low loading of drugs. We have synthesized hollow mesoporous silica (HMS)@MOF capsule that can be used as pH-responsive drug delivery system for anti-cancer drug doxorubicin (DOX). DOX is loaded into the inner cavity of HMS.Then, zeolitic imidazolate framework-8 (ZIF-8) nanoparticles are coated on the outer surface of DOX loaded HMS...
January 16, 2018: ChemMedChem
Francesca Moraca, David Rinaldo, Amos Brittain Smith, Cameron Abrams
The small molecule CD4 mimetics (smCD4mc) are a class of highly potent HIV-1 entry inhibitors characterized by a unique SAR. They share a halogenated phenyl ring (region 1) that deeply inserts into an otherwise water-filled cavity at the CD4 binding site on the gp120 surface, so-called F43 cavity. Conservative modifications to region 1 away from this halogenated phenyl motif have all lead to loss of activity, despite they are predicted to bind equally well via standard empirical computational approaches making difficult to further optimize this region of the compounds to increase binding to gp120...
January 16, 2018: ChemMedChem
Marco Paolino, Margherita Brindisi, Alessandra Vallone, Stefania Butini, Giusepp Campiani, Chiara Nannicini, Germano Giuliani, Maurizio Anzini, Stefania Lamponi, Gianluca Giorgi, Diego Sbardella, Davide M Ferraris, Stefano Marini, Massimo Coletta, Ivana Palucci, Mariachiara Minerva, Giovanni Delogu, Ilaria Pepponi, Delia Goletti, Andrea Cappelli, Sandra Gemma, Simone Brogi
The enzyme Zmp1 is a zinc-peptidase having a critical role in M. tuberculosis pathogenicity. Here we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, 1c was the most potent Zmp1 inhibitor known to date, and its binding mode was analysed both through kinetic studies and molecular modelling, identifying critical interactions of 1c with the zinc-ion and residues in the active site. Effect of 1c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M...
January 15, 2018: ChemMedChem
Alex George Baldwin, Victor S Tapia, Tessa Swanton, Claire S White, James A Beswick, David Brough, Sally Freeman
The NLRP3 inflammasome is an important regulator of the sterile inflammatory response and its activation by host-derived sterile molecules leads to the intracellular activation of caspase-1, processing of the pro-inflammatory cytokines interleukin-1β (IL 1β)/IL-18, and pyroptotic cell death. Inappropriate activation of NLRP3 drives a chronic inflammatory response and is implicated in several non-communicable diseases, including gout, atherosclerosis, type II diabetes and Alzheimer's disease. In this study, we report the design, synthesis and biological evaluation of novel boron compounds (NBCs) as NLRP3 inflammasome inhibitors...
January 13, 2018: ChemMedChem
Gilles Ouvry, Nicolas Atrux-Tallau, Franck Bihl, Aline Bondu, Claire Bouix-Peter, Isabelle Carlavan, Olivier Christin, Marie-Josée Cuadrado, Claire Defoin-Platel, Sophie Deret, Denis Duvert, Christophe Feret, Mathieu Forissier, Jean-François Fournier, David Froude, Fériel Hacini-Rachinel, Craig Steven Harris, Catherine Hervouet, Hélène Huguet, Guillaume Lafitte, Anne-Pascale Luzy, Branislav Musicki, Danielle Orfila, Benjamin Ozello, Coralie Pascau, Jonathan Pascau, Véronique Parnet, Guillaume Peluchon, Romain Pierre, David Piwnica, Catherine Raffin, Patricia Rossio, Delphine Spiesse, Nathalie Taquet, Etienne Thoreau, Rodolphe Vatinel, Emmanuel Vial, Laurent François Hennequin
With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a very sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated with the discovery of CD12681 (compound 14; N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide), a potent inverse agonist with in vivo activity in an IL-23 induced skin inflammation model in mouse...
January 12, 2018: ChemMedChem
Xinshan Ye, Qin Li
It is important to find more effective and safer immunosuppressants because the clinically-used immunosuppressive agents have significant side-effects. A series of N-substituted iminosugar derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by CCK-8 assay. The results revealed that iminosugars 10e and 10i exhibited the strongest inhibitory effect on mouse splenocyte proliferation (IC50 = 2.16 and 2.48 μM, respectively), whereas the iminosugars containing an amide group near the hydrophilic head (compounds 10j-n) exhibited no inhibitory effects...
January 11, 2018: ChemMedChem
Chonny Herrera-Acevedo, Luciana Scotti, Marcus Tullius Scotti
Chagas disease is an endemic disease caused by Trypanosoma cruzi, which affects more than eight million people, mostly in the Americas. A search for new treatments is necessary to control and eliminate this disease. Sesquiterpene lactones (SLs) are an interesting group of secondary metabolites characteristic of Asteraceae that have presented a wide range of biological activities. From the ChEMBL database, we selected a diverse set of 4,452, 1,635 and 1,322 structures with tested activity against the three T...
January 11, 2018: ChemMedChem
Joanna Gałęzowska
Bisphosphonates (BPs) are well established, widely used first-choice drugs for bone-related diseases and are one of the few classes of molecules for selective bone-targeting. Their binding to calcium cations within hydroxyapatite (HA) is a key physico-chemical event taking place on the bone surface. It is the starting point for a cascade of biochemical reactions and cellular effects that lead to the pharmacological activity of BPs. The phenomenon is known for years, yet still its physicochemical nature is not fully understood...
January 11, 2018: ChemMedChem
Masaki Ohtawa, Shiho Arima, Naoki Ichida, Tomiaki Terayama, Hironao Ohno, Takaya Yamazaki, Taichi Ohshiro, Noriko Sato, Satoshi Omura, Hiroshi Tomoda, Tohru Nagamitsu
Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO-1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O-acyltransferase 2 (SOAT2). To aid in the development of new cholesterol-lowering or antiatherosclerotic agents, new A-ring simplified pyripyropene A analogs were designed and synthesized based on the total synthesis and the results of the structure-activity relationship studies of pyripyropene A achieved by our group. Among the analogs, two A-ring simplified pyripyropene A analogs exhibited equally efficient SOAT2 inhibitory activity compared with that of natural pyripyropene A...
January 11, 2018: ChemMedChem
Sergej Šesták, Maroš Bella, Tomáš Klunda, Soňa Gurská, Petr Džubák, Florian Wöls, Iain Bh Wilson, Vladimir Sladek, Marián Hajdúch, Monika Polakova, Juraj Kóňa
Inhibition of biosynthesis of complex N-glycans in Golgi apparatus influence progress of tumor growth and metastasis. Golgi α-mannosidase II (GMII) has become a therapeutic target for a drug with anticancer activities. One critical task for successful application GMII drugs in medicine treatment is to reduce their unwanted co-inhibition with lysosomal α-mannosidase (LMan) by which suffer all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α-mannosidases from Drosophila melanogaster (GMIIb and LManII)...
January 11, 2018: ChemMedChem
Rajesh Varkhedkar, Shalini Dogra, Divya Tiwari, Yusuf Hussain, Prem Narayan Yadav, Ganesh Pandey
Muscarinic acetylcholine receptors (mAChRs) are important therapeutic targets for several diseases of central nervous system and periphery. However, lack of subtype selective ligands of these receptors is a major challenge. A novel approach of integrating natural product framework with bioactive molecule (iNPBM) by utilizing the Gephyrotoxin and isoindoline framework, is demonstrated for discovery of new and selective mAChR modulators. We established a scalable and versatile synthetic scheme to enable synthesis of various analogues that provided the first SAR study of this class of compounds...
January 10, 2018: ChemMedChem
Hiromi Ii, Taku Yoshiya, Susumu Nakata, Keiko Taniguchi, Koushi Hidaka, Shugo Tsuda, Masayoshi Mochizuki, Yuji Nishiuchi, Yuko Tsuda, Kosei Ito, Susumu Kageyama, Tatsuhiro Yoshiki
γ-Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester-type cell-permeable prodrug, pro-GA, was developed based on the structure of N-glutaryl-l-alanine (GA), by structure optimization using temporary fluorophore-tagged prodrug candidates. The antiproliferative activity of pro-GA was demonstrated using GGCT-overexpressing NIH-3T3 cells and human cancer cells including MCF7, HL-60, and PC3 cells...
January 9, 2018: ChemMedChem
Demetra Sm Chatzileontiadou, Aikaterini C Tsika, Zoi Diamantopoulou, Jean Delbé, Josette Badet, José Courty, Vassiliki T Skamnaki, Vanessa Parmenopoulou, Dimitri Komiotis, Joseph M Hayes, Georgios A Spyroulias, Demetres D Leonidas
A member of Ribonuclease A superfamily, human Angiogenin (hAng) is a potent angiogenic factor. Heteronuclear NMR spectroscopy combined with induced-fit docking revealed a dual binding mode for the most antiangiogenic compound of a series of ribofuranosyl pyrimidine nucleosides that strongly inhibit hAng's angiogenic activity in vivo. While modelling suggests the potential of a simultaneous binding of the inhibitors at the active and cell binding sites, NMR indicates greater affinity for the cell binding site than for the active site...
January 4, 2018: ChemMedChem
Govind S Bhosle, Shalmali Kharche, Santosh Kumar, Durba Sengupta, Souvik Maiti, Moneesha Fernandes
We report a hundred-fold increase in binding affinity of the Tat(48-57) peptide to HIV-1 TAR RNA by replacing R52, an essential and critical residue for Tat's specific binding, by (2S,4S)-4-guanidinoproline. The resulting αTat1M peptide is a far superior binder than γTat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)-proline, or even the control Tat (CtrlTat) itself. Our observations are supported by CD, ITC, gel electrophoresis and UV spectroscopy studies...
January 4, 2018: ChemMedChem
Val Gillet, Matthew P Seddon, David A Cosgrove
Bioisosterism is an important concept in the lead optimization phase of drug discovery where the aim is to make modifications to parts of a molecule with the aim of improving some properties while maintaining others. We present an analysis of bioisosteric fragments extracted from the ligands in an established data set consisting of 121 protein targets. A pairwise analysis is carried out of all ligands for a given target. The ligands are fragmented using the BRICS fragmentation scheme and a pair of fragments is deemed to be bioisosteric if they occupy a similar volume of the protein binding site...
January 3, 2018: ChemMedChem
Manuela Basso, Huan Huan Chen, Debasmita Tripathy, Mariarosaria Conte, Kim Y P Apperley, Angela De Simone, Jeffrey W Keillor, Rajiv Ratan, Angela Nebbioso, Federica Sarno, Lucia Altucci, Andrea Milelli
In recent years there has been a clear consensus that neurodegenerative conditions can be better treated through concurrent modulation of different targets. Herein, we report that combined inhibition of Transglutaminase 2 (TG2) and Histone Deacetylases (HDACs) protects synergistically against toxic stimuli mediated by glutamate. Based on these findings, we designed and synthesized a series of novel dual TG2-HDAC binding agents. Compound 3 emerges as the most interesting of the series being able to inhibit TG2 and HDACs both in vitro (TG2, IC50 = 13...
December 29, 2017: ChemMedChem
Conrad Stork, Johannes Wagner, Nils-Ole Friedrich, Christina de Bruyn Kops, Martin Šícho, Johannes Kirchmair
False-positive assay readouts caused by badly behaving compounds (frequent hitters, pan-assay interference compounds - PAINS, aggregators and others) continue to pose a major challenge to experimental screening. Few in silico methods exist that allow the prediction of such problematic compounds. We report on the development of Hit Dexter, two extremely randomized trees classifiers for the prediction of compounds likely to trigger positive assay readouts either by true promiscuity or by assay interference. The models were trained on a well-prepared dataset extracted from the PubChem Bioassay database, consisting of approximately 311k compounds tested for activity on at least 50 proteins...
December 29, 2017: ChemMedChem
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