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Fragment Based Lead Discovery

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...
December 29, 2016: ACS Chemical Biology
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
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
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...
November 11, 2016: Trends in Pharmacological Sciences
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
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
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
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 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
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
Vladimiras Oleinikovas, Giorgio Saladino, Benjamin P Cossins, Francesco L Gervasio
Cryptic pockets, i.e. sites on protein targets that only become apparent when drugs bind, provide a promising alternative to classical binding sites for drug development. Here we investigate the nature and dynamical properties of cryptic sites in four pharmacologically relevant targets, while comparing the efficacy of various simulation-based approaches in discovering them. We find that the studied cryptic sites do not correspond to local minima in the computed conformational free energy landscape of the unliganded proteins...
October 11, 2016: Journal of the American Chemical Society
Jamil Al-Asri, Gyöngyi Gyémánt, Erika Fazekas, Gábor Lehoczki, Matthias F Melzig, Gerhard Wolber, Jérémie Mortier
Better control of postprandial hyperglycemia can be achieved by delaying the absorption of glucose resulting from carbohydrate digestion. Because α-amylase initiates the hydrolysis of polysaccharides, the design of α-amylase inhibitors can lead to the development of new treatments for metabolic disorders such as type II diabetes and obesity. In this study, a rational computer-aided approach was developed to identify novel α-amylase inhibitors. Three-dimensional pharmacophores were developed based on the binding mode analysis of six different families of compounds that bind to this enzyme...
October 11, 2016: ChemMedChem
Michiko Tawada, Shinkichi Suzuki, Yasuhiro Imaeda, Hideyuki Oki, Gyorgy Snell, Craig A Behnke, Mitsuyo Kondo, Naoki Tarui, Toshimasa Tanaka, Takanobu Kuroita, Masaki Tomimoto
A novel approach was conducted for fragment-based lead discovery and applied to renin inhibitors. The biochemical screening of a fragment library against renin provided the hit fragment which showed a characteristic interaction pattern with the target protein. The hit fragment bound only to the S1, S3, and S3(SP) (S3 subpocket) sites without any interactions with the catalytic aspartate residues (Asp32 and Asp215 (pepsin numbering)). Prior to making chemical modifications to the hit fragment, we first identified its essential binding sites by utilizing the hit fragment's substructures...
September 28, 2016: Bioorganic & Medicinal Chemistry
Volodimir Olexiouk, Gerben Menschaert
The identification of small proteins and peptides has consistently proven to be challenging. However, technological advances as well as multi-omics endeavors facilitate the identification of novel small coding sequences, leading to new insights. Specifically, the application of next generation sequencing technologies (NGS), providing accurate and sample specific transcriptome / translatome information, into the proteomics field led to more comprehensive results and new discoveries. This book chapter focuses on the inclusion of RNA-Seq and RIBO-Seq also known as ribosome profiling, an RNA-Seq based technique sequencing the +/- 30 bp long fragments captured by translating ribosomes...
2016: Advances in Experimental Medicine and Biology
Yikai Wang, Jean-Yves Wach, Patrick Sheehan, Cheng Zhong, Chenyang Zhan, Richard Harris, Steven C Almo, Joshua Bishop, Stephen J Haggarty, Alexander Ramek, Kayla N Berry, Conor O'Herin, Angela N Koehler, Alvin W Hung, Damian W Young
Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure-activity relationship, and finally lead to the synthesis of a more potent compound.
September 8, 2016: ACS Medicinal Chemistry Letters
Disha Patel, Janet Antwi, Pratibha C Koneru, Erik Serrao, Stefano Forli, Jacques J Kessl, Lei Feng, Nanjie Deng, Ronald M Levy, James R Fuchs, Arthur J Olson, Alan N Engelman, Joseph D Bauman, Mamuka Kvaratskhelia, Eddy Arnold
HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors...
November 4, 2016: Journal of Biological Chemistry
Zheng Li, Jianyong Yang, Xuekun Wang, Huilan Li, Chunxia Liu, Nasi Wang, Wenlong Huang, Hai Qian
The free fatty acid receptor 1 (FFA1/GPR40) is a novel antidiabetic target based on particular mechanism in enhancing glucose-stimulated insulin secretion. Most of reported FFA1 agonists, however, have been suffered from relatively high lipophilicity and molecular weight. Aiming to develop potent agonists with improved physicochemical property, 25 compounds containing triazole scaffold and various carboxylic acid fragments were synthesized via the click chemistry. Among them, the optimal lead compound 26 with relatively low lipophicity (LogD7...
November 1, 2016: Bioorganic & Medicinal Chemistry
Angelo M Reggiani, Elena Simoni, Roberta Caporaso, Johann Meunier, Emeline Keller, Tangui Maurice, Anna Minarini, Michela Rosini, Andrea Cavalli
Alzheimer's disease (AD) is a chronic pathological condition that leads to neurodegeneration, loss of intellectual abilities, including cognition and memory, and ultimately to death. It is widely recognized that AD is a multifactorial disease, where different pathological cascades (mainly amyloid and tau) contribute to neural death and to the clinical outcome related to the disease. The currently available drugs for AD were developed according to the one-target, one-drug paradigm. In recent times, multi-target strategies have begun to play an increasingly central role in the discovery of more efficacious candidates for complex neurological conditions, including AD...
2016: Scientific Reports
David G Twigg, Noriyasu Kondo, Sophie L Mitchell, Warren R J D Galloway, Hannah F Sore, Andrew Madin, David R Spring
Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp(2) -rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp(3) character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters...
September 26, 2016: Angewandte Chemie
Chun-Feng Chang, Wen-Hsing Lin, Yi-Yu Ke, Yih-Shyan Lin, Wen-Chieh Wang, Chun-Hwa Chen, Po-Chu Kuo, John T A Hsu, Biing-Jiun Uang, Hsing-Pang Hsieh
Aurora kinases have emerged as important anticancer targets so that there are several inhibitors have advanced into clinical study. Herein, we identified novel indazole derivatives as potent Aurora kinases inhibitors by utilizing in silico fragment-based approach and knowledge-based drug design. After intensive hit-to-lead optimization, compounds 17 (dual Aurora A and B), 21 (Aurora B selective) and 30 (Aurora A selective) possessed indazole privileged scaffold with different substituents, which provide sub-type kinase selectivity...
November 29, 2016: European Journal of Medicinal Chemistry
Chao Chen, Hugh Zhu, Frédéric Stauffer, Giorgio Caravatti, Susanne Vollmer, Rainer Machauer, Philipp Holzer, Henrik Möbitz, Clemens Scheufler, Martin Klumpp, Ralph Tiedt, Kim S Beyer, Keith Calkins, Daniel Guthy, Michael Kiffe, Jeff Zhang, Christoph Gaul
Oncogenic MLL fusion proteins aberrantly recruit Dot1L, a histone methyltransferase, to ectopic loci, leading to local hypermethylation of H3K79 and misexpression of HoxA genes driving MLL-rearranged leukemias. Inhibition of the methyltransferase activity of Dot1L in this setting is predicted to reverse aberrant H3K79 methylation, leading to repression of leukemogenic genes and tumor growth inhibition. In the context of our Dot1L drug discovery program, high-throughput screening led to the identification of 2, a weak Dot1L inhibitor with an unprecedented, induced pocket binding mode...
August 11, 2016: ACS Medicinal Chemistry Letters
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