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Fragment Based Lead Discovery

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https://www.readbyqxmd.com/read/28339199/structure-based-discovery-of-new-antagonist-and-biased-agonist-chemotypes-for-the-kappa-opioid-receptor
#1
Zhong Zheng, Xi-Ping Huang, Thomas J Mangano, Rodger Zou, Xin Chen, Saheem Zaidi, Bryan L Roth, Raymond C Stevens, Vsevolod Katritch
The ongoing epidemics of opioid overdose raises an urgent need for effective anti-addiction therapies and addiction-free painkillers. The κ-opioid receptor (KOR) has emerged as a promising target for both indications, raising demand for new chemotypes of KOR antagonists, as well as G-protein-biased agonists. We employed the crystal structure of the KOR-JDTic complex and ligand-optimized structural templates to perform virtual screening of available compound libraries for new KOR ligands. The prospective virtual screening campaign yielded a high 32% hit rate, identifying novel fragment-like and lead-like chemotypes of KOR ligands...
March 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28291329/intracellular-delivery-using-nanosecond-laser-excitation-of-large-area-plasmonic-substrates
#2
Nabiha Saklayen, Marinus Huber, Marinna Madrid, Valeria Nuzzo, Daryl I Vulis, Weilu Shen, Jeffery Nelson, Arthur A McClelland, Alexander Heisterkamp, Eric Mazur
Efficiently delivering functional cargo to millions of cells on the time scale of minutes will revolutionize gene therapy, drug discovery, and high-throughput screening. Recent studies of intracellular delivery with thermoplasmonic structured surfaces show promising results but in most cases require time- or cost-intensive fabrication or lead to unreproducible surfaces. We designed and fabricated large-area (14 × 14 mm), photolithography-based, template-stripped plasmonic substrates that are nanosecond laser-activated to form transient pores in cells for cargo entry...
March 22, 2017: ACS Nano
https://www.readbyqxmd.com/read/28273150/identification-of-small-molecule-inhibitors-for-influenza-a-virus-using-in-silico-and-in-vitro-approaches
#3
Juliann Nzembi Makau, Ken Watanabe, Takeshi Ishikawa, Satoshi Mizuta, Tsuyoshi Hamada, Nobuyuki Kobayashi, Noriyuki Nishida
Influenza viruses have acquired resistance to approved neuraminidase-targeting drugs, increasing the need for new drug targets for the development of novel anti-influenza drugs. Nucleoprotein (NP) is an attractive target since it has an indispensable role in virus replication and its amino acid sequence is well conserved. In this study, we aimed to identify new inhibitors of the NP using a structure-based drug discovery algorithm, named Nagasaki University Docking Engine (NUDE), which has been established especially for the Destination for GPU Intensive Machine (DEGIMA) supercomputer...
2017: PloS One
https://www.readbyqxmd.com/read/28240184/from-protein-structure-to-small-molecules-recent-advances-and-applications-to-fragment-based-drug-discovery
#4
Leonardo G Ferreira, Adriano D Andricopulo
Fragment-based drug discovery (FBDD) is a broadly used strategy in structure-guided ligand design, whereby low-molecular weight hits move from lead-like to drug-like compounds. Over the past 15 years, an increasingly important role of the integration of these strategies into industrial and academic research platforms has been successfully established, allowing outstanding contributions to drug discovery. One important factor for the current prominence of FBDD is the better coverage of the chemical space provided by fragment-like libraries...
February 24, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28186401/chemoproteomic-screening-of-covalent-ligands-reveals-uba5-as-a-novel-pancreatic-cancer-target
#5
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28171830/a-review-on-antioxidant-potential-of-bioactive-heterocycle-benzofuran-natural-and-synthetic-derivatives
#6
REVIEW
Karam Chand, Rajeshwari, Asha Hiremathad, Mahak Singh, M Amelia Santos, Rangappa S Keri
The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. In this context, oxygen heterocycles exhibit diverse biological and pharmacological activities due in part to the similarities with many natural and synthetic molecules with known biological activity. Among oxygen containing heterocycles, benzofuran (synthetic and natural isolated) and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as pharmacological agents such as antioxidant, antitumor, antiplatelet, antimalarial, antiinflammatory, antidepressant and anticonvulsant properties...
April 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28157311/structure-based-library-design-and-fragment-screening-for-the-identification-of-reversible-complement-factor-d-protease-inhibitors
#7
Anna Vulpetti, Stefan Randl, Simon Rüdisser, Nils Ostermann, Paul Erbel, Aengus Mac Sweeney, Thomas Zoller, Bahaa Salem, Bernd Gerhartz, Frederic Cumin, Ulrich Hommel, Claudio Dalvit, Edwige Lorthiois, Jürgen Maibaum
Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries...
February 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28117408/swath-based-proteomics-identified-carbonic-anhydrase-2-as-a-potential-diagnosis-biomarker-for-nasopharyngeal-carcinoma
#8
Yanzhang Luo, Tin Seak Mok, Xiuxian Lin, Wanling Zhang, Yizhi Cui, Jiahui Guo, Xing Chen, Tao Zhang, Tong Wang
Nasopharyngeal carcinoma (NPC) is a serious threat to public health, and the biomarker discovery is of urgent needs. The data-independent mode (DIA) based sequential window acquisition of all theoretical fragment-ion spectra (SWATH) mass spectrometry (MS) has been proved to be precise in protein quantitation and efficient for cancer biomarker researches. In this study, we performed the first SWATH-MS analysis comparing the NPC and normal tissues. Spike-in stable isotope labeling by amino acids in cell culture (super-SILAC) MS was used as a shotgun reference...
January 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28106992/discovery-of-n-pyridin-4-yl-1-5-naphthyridin-2-amines-as-potential-tau-pathology-pet-tracers-for-alzheimer-s-disease
#9
Frederik J R Rombouts, José-Ignacio Andrés, Manuela Ariza, José Manuel Alonso, Nigel Austin, Astrid Bottelbergs, Lu Chen, Vladimir Chupakhin, Erna Cleiren, Katleen Fierens, Alberto Fontana, Xavier Langlois, Joseph E Leenaerts, Jonas Mariën, Carolina Martínez Lamenca, Rhys Salter, Mark E Schmidt, Paula Te Riele, Cindy Wintmolders, Andrés A Trabanco, Wei Zhang, Gregor Macdonald, Dieder Moechars
A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28097765/a-false-positive-screening-hit-in-fragment-based-lead-discovery-watch-out-for-the-red-herring
#10
Jonathan Cramer, Johannes Schiebel, Tobias Wulsdorf, Kristof Grohe, Eszter Eva Najbauer, Frederik R Ehrmann, Nedyalka Radeva, Nina Zitzer, Uwe Linne, Rasmus Linser, Andreas Heine, Gerhard Klebe
With the rising popularity of fragment-based approaches in drug development, more and more attention has to be devoted to the detection of false-positive screening results. In particular, the small size and low affinity of fragments drives screening techniques to their limit. The pursuit of a false-positive hit can cause significant loss of time and resources. Here, we present an instructive and intriguing investigation into the origin of misleading assay results for a fragment that emerged as the most potent binder for the aspartic protease endothiapepsin (EP) across multiple screening assays...
January 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28095828/improved-genome-sequencing-using-an-engineered-transposase
#11
Amirali Kia, Christian Gloeckner, Trina Osothprarop, Niall Gormley, Erin Bomati, Michelle Stephenson, Igor Goryshin, Molly Min He
BACKGROUND: Next-generation sequencing (NGS) has transformed genomic research by reducing turnaround time and cost. However, no major breakthrough has been made in the upstream library preparation methods until the transposase-based Nextera method was invented. Nextera combines DNA fragmentation and barcoding in a single tube reaction and therefore enables a very fast workflow to sequencing-ready DNA libraries within a couple of hours. When compared to the traditional ligation-based methods, transposed-based Nextera has a slight insertion bias...
January 17, 2017: BMC Biotechnology
https://www.readbyqxmd.com/read/28032980/ligand-discovery-for-a-peptide-binding-gpcr-by-structure-based-screening-of-fragment-and-lead-like-chemical-libraries
#12
Anirudh Ranganathan, Philipp Heine, Axel Rudling, Andreas Plückthun, Lutz Kummer, Jens Carlsson
Peptide-recognizing G protein-coupled receptors (GPCRs) are promising therapeutic targets but often resist drug discovery efforts. Determination of crystal structures for peptide-binding GPCRs has provided opportunities to explore structure-based methods in lead development. Molecular docking screens of two chemical libraries, containing either fragment- or lead-like compounds, against a neurotensin receptor 1 crystal structure allowed for a comparison between different drug development strategies for peptide-binding GPCRs...
January 24, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/27935308/combining-molecular-scaffolds-from-fda-approved-drugs-application-to-drug-discovery
#13
Richard D Taylor, Malcolm MacCoss, Alastair D G Lawson
We have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in silico database of approximately 14 million molecules. This virtual library was compared with molecular databases of published and commercially available compounds to assess the prevalence of drug ring combinations in modern medicinal chemistry and to identify areas of under-represented, but clinically validated, chemical space. From the 10 trillion molecular comparisons, we found that less than 1% of the possible combinations of drug ring systems appear in commercially available libraries...
December 23, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27916639/binding-thermodynamics-discriminates-fragments-from-druglike-compounds-a-thermodynamic-description-of-fragment-based-drug-discovery
#14
REVIEW
Glyn Williams, György G Ferenczy, Johan Ulander, György M Keserű
Small is beautiful - reducing the size and complexity of chemical starting points for drug design allows better sampling of chemical space, reveals the most energetically important interactions within protein-binding sites and can lead to improvements in the physicochemical properties of the final drug. The impact of fragment-based drug discovery (FBDD) on recent drug discovery projects and our improved knowledge of the structural and thermodynamic details of ligand binding has prompted us to explore the relationships between ligand-binding thermodynamics and FBDD...
December 1, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27842887/molecular-networking-as-a-drug-discovery-drug-metabolism-and-precision-medicine-strategy
#15
REVIEW
Robert A Quinn, Louis-Felix Nothias, Oliver Vining, Michael Meehan, Eduardo Esquenazi, Pieter C Dorrestein
Molecular networking is a tandem mass spectrometry (MS/MS) data organizational approach that has been recently introduced in the drug discovery, metabolomics, and medical fields. The chemistry of molecules dictates how they will be fragmented by MS/MS in the gas phase and, therefore, two related molecules are likely to display similar fragment ion spectra. Molecular networking organizes the MS/MS data as a relational spectral network thereby mapping the chemistry that was detected in an MS/MS-based metabolomics experiment...
February 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/27808502/n-glycopeptide-reduction-with-exoglycosidases-enables-accurate-characterization-of-site-specific-n-glycosylation
#16
Rui Chen, Kai Cheng, Zhibin Ning, Daniel Figeys
We report a new approach called NGlycoReduction that generates an oligomannosylated N-glycopeptidome by enzymatically removing sugars outside the N-glycopeptide pentasaccharide core with exoglycosidases. This approach is based on our discovery that the fragmentation of glycopeptides is glycan-structure dependent and glycans with core mannose structures overwhelmingly lead to the generation of Y1 ions when subjected to MS/MS in mass spectrometry. Oligomannosylated glycopeptidome produced by NGlycoReduction can be mixed with the intact N-glycopeptidome and analyzed by HPLC-ESI-MS together to enable the identification of peptide sequence, glycosylation site and the structure of intact glycopeptides...
December 6, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/27752253/cytological-profile-of-antibacterial-ftsz-inhibitors-and-synthetic-peptide-mciz
#17
Lidia Araújo-Bazán, Laura B Ruiz-Avila, David Andreu, Sonia Huecas, José M Andreu
Cell division protein FtsZ is the organizer of the cytokinetic ring in almost all bacteria and a target for the discovery of new antibacterial agents that are needed to counter widespread antibiotic resistance. Bacterial cytological profiling, using quantitative microscopy, is a powerful approach for identifying the mechanism of action of antibacterial molecules affecting different cellular pathways. We have determined the cytological profile on Bacillus subtilis cells of a selection of small molecule inhibitors targeting FtsZ on different binding sites...
2016: Frontiers in Microbiology
https://www.readbyqxmd.com/read/27750202/discovery-of-novel-dengue-virus-ns5-methyltransferase-non-nucleoside-inhibitors-by-fragment-based-drug-design
#18
Fatiha Benmansour, Iuni Trist, Bruno Coutard, Etienne Decroly, Gilles Querat, Andrea Brancale, Karine Barral
With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27748000/computational-design-of-novel-inhibitors-to-overcome-weed-resistance-associated-with-acetohydroxyacid-synthase-ahas-p197l-mutant
#19
Ren-Yu Qu, Jing-Fang Yang, Yu-Chao Liu, Qiong Chen, Ge-Fei Hao, Cong-Wei Niu, Zhen Xi, Guang-Fu Yang
BACKGOUND: Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application of AHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS. RESULTS: Pyrimidinyl salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant...
October 17, 2016: Pest Management Science
https://www.readbyqxmd.com/read/27739691/fragment-to-lead-medicinal-chemistry-publications-in-2015
#20
Christopher N Johnson, Daniel A Erlanson, Christopher W Murray, David C Rees
Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will provide a useful point of reference for both FBDD practitioners and the wider medicinal chemistry community.
October 14, 2016: Journal of Medicinal Chemistry
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