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Fragment Based Lead Discovery

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https://www.readbyqxmd.com/read/28495381/a-fragment-based-approach-leading-to-the-discovery-of-a-novel-binding-site-and-the-selective-ck2-inhibitor-cam4066
#1
Claudia De Fusco, Paul Brear, Jessica Iegre, Kathy Hadje Georgiou, Hannah F Sore, Marko Hyvönen, David R Spring
Recently we reported the discovery of a potent and selective CK2α inhibitor CAM4066. This compound inhibits CK2 activity by exploiting a pocket located outside the ATP binding site (αD pocket). Here we describe in detail the journey that led to the discovery of CAM4066 using the challenging fragment linking strategy. Specifically, we aimed to develop inhibitors by linking a high-affinity fragment anchored in the αD site to a weakly binding warhead fragment occupying the ATP site. Moreover, we describe the remarkable impact that molecular modelling had on the development of this novel chemical tool...
April 30, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28492317/discovery-of-a-potent-non-peptidomimetic-small-molecule-antagonist-of-cellular-inhibitor-of-apoptosis-protein-1-ciap1-and-x-linked-inhibitor-of-apoptosis-protein-xiap
#2
Emiliano Tamanini, Ildiko Maria Buck, Gianni Chessari, Elisabetta Chiarparin, James E H Day, Martyn Frederickson, Charlotte M Griffiths-Jones, Keisha Hearn, Tom D Heightman, Aman Iqbal, Christopher Norbert Johnson, Edward J Lewis, Vanessa Martins, Torren Peakman, Michael Reader, Sharna J Rich, George A Ward, Pamela A Williams, Nicola E Wilsher
XIAP and cIAP1 are members of the inhibitor of apoptosis protein (IAP) family and are key regulators of anti-apoptotic and pro-survival signaling pathways. Overexpression of IAPs occurs in various cancers and has been associated with tumor progression and resistance to treatment. Structure-based drug design (SBDD) guided by structural information from X-ray crystallography, computational studies and NMR solution conformational analysis was successfully applied to a fragment-derived lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist of XIAP and cIAP1 and a structurally novel chemical probe for IAP biology...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28475301/label-free-quantification-of-intracellular-mitochondrial-dynamics-using-dielectrophoresis
#3
Ali Rohani, John H Moore, Jennifer A Kashatus, Hiromi Sesaki, David F Kashatus, Nathan S Swami
Mitochondrial dynamics play an important role within several pathological conditions, including cancer and neurological diseases. For the purpose of identifying therapies that target aberrant regulation of the mitochondrial dynamics machinery and characterizing the regulating signaling pathways, there is a need for label-free means to detect the dynamic alterations in mitochondrial morphology. We present the use of dielectrophoresis for label-free quantification of intracellular mitochondrial modifications that alter cytoplasmic conductivity, and these changes are benchmarked against label-based image analysis of the mitochondrial network...
May 15, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28437091/speeding-up-early-drug-discovery-in-antiviral-research-a-fragment-based-in-silico-approach-for-the-design-of-virtual-anti-hepatitis-c-leads
#4
Alejandro Speck-Planche, M Natália Dias Soeiro Cordeiro
Hepatitis C constitutes an unresolved global health problem. This infectious disease is caused by the hepatotropic hepatitis C virus (HCV), and it can lead to the occurrence of life-threatening medical conditions, such as cirrhosis and liver cancer. Nowadays, major clinical concerns have arisen because of the appearance of multidrug resistance (MDR) and the side effects especially associated with long-term treatments. In this work, we report the first multitasking model for quantitative structure-biological effect relationships (mtk-QSBER), focused on the simultaneous exploration of anti-HCV activity and in vitro safety profiles related to the absorption, distribution, metabolism, elimination, and toxicity (ADMET)...
May 1, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28414463/do-fragments-and-crystallization-additives-bind-similarly-to-drug-like-ligands
#5
Malgorzata N Drwal, Célien Jacquemard, Carlos Perez, Jérémy Desaphy, Esther Kellenberger
The success of fragment-based drug design (FBDD) hinges upon the optimization of low molecular weight compounds (MW<300) with weak binding affinities to lead compounds with high affinity and selectivity. Usually, structural information from fragment-protein complexes is used to develop ideas about the binding mode of similar, but drug-like molecules. In this regard, crystallization additives such as cryoprotectants or buffer components, highly abundant in crystal structures, are frequently ignored. Thus, the aim of the study was the investigation of the information present in both protein complexes with fragments as well as additives and how they relate to the binding modes of their drug-like counterparts...
April 17, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28406299/discovery-and-optimization-of-isoquinoline-ethyl-ureas-as-antibacterial-agents
#6
Philippe Panchaud, Thierry Bruyère, Anne-Catherine Blumstein, Daniel Bur, Alain Chambovey, Eric A Ertel, Markus Gude, Christian Hubschwerlen, Loïc Jacob, Thierry Kimmerlin, Thomas Pfeifer, Lars Prade, Peter Seiler, Daniel Ritz, Georg Rueedi
Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site...
May 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28350444/bottom-up-elucidation-of-glycosidic-bond-stereochemistry
#7
Christopher J Gray, Baptiste Schindler, Lukasz G Migas, Martina Pičmanová, Abdul R Allouche, Anthony P Green, Santanu Mandal, Mohammed S Motawia, Raquel Sánchez-Pérez, Nanna Bjarnholt, Birger L Møller, Anouk M Rijs, Perdita E Barran, Isabelle Compagnon, Claire E Eyers, Sabine L Flitsch
The lack of robust, high-throughput, and sensitive analytical strategies that can conclusively map the structure of glycans has significantly hampered progress in fundamental and applied aspects of glycoscience. Resolution of the anomeric α/β glycan linkage within oligosaccharides remains a particular challenge. Here, we show that "memory" of anomeric configuration is retained following gas-phase glycosidic bond fragmentation during tandem mass spectrometry (MS(2)). These findings allow for integration of MS(2) with ion mobility spectrometry (IM-MS(2)) and lead to a strategy to distinguish α- and β-linkages within natural underivatized carbohydrates...
April 6, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28339199/structure-based-discovery-of-new-antagonist-and-biased-agonist-chemotypes-for-the-kappa-opioid-receptor
#8
Zhong Zheng, Xi-Ping Huang, Thomas J Mangano, Rodger Zou, Xin Chen, Saheem A Zaidi, Bryan L Roth, Raymond C Stevens, Vsevolod Katritch
The ongoing epidemics of opioid overdose raises an urgent need for effective antiaddiction 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...
April 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28291329/intracellular-delivery-using-nanosecond-laser-excitation-of-large-area-plasmonic-substrates
#9
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...
April 25, 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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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