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Fragment Based Lead Discovery

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https://www.readbyqxmd.com/read/29193967/structure-guided-discovery-of-novel-potent-and-orally-bioavailable-inhibitors-of-lipoprotein-associated-phospholipase-a2
#1
Qiufeng Liu, Fubao Huang, Xiao-Jing Yuan, Kai Wang, Yi Zou, Jianhua Shen, Yechun Xu
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with 300-fold potency improvement. By the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar activity were obtained...
December 1, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#2
Paola Di Lello, Richard Pastor, Jeremy M Murray, Robert A Blake, Frederick Cohen, Terry D Crawford, Joy Drobnick, Jason Drummond, Lorna Kategaya, Tracy Kleinheinz, Till Maurer, Lionel Rouge, Xianrui Zhao, Ingrid Wertz, Chudi Ndubaku, Vickie Tsui
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53 and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)-phenol compounds described by Kategaya et al.1 as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29158831/identification-and-validation-of-a-salivary-protein-panel-to-detect-heart-failure-early
#3
Xi Zhang, Terry Walsh, John J Atherton, Karam Kostner, Benjamin Schulz, Chamindie Punyadeera
BACKGROUND: Over 26 million people suffer from heart failure (HF) globally. Current diagnosis of HF relies on clinical evaluation, blood assays and imaging techniques. Our aim is to develop a diagnostic assay to detect HF in at risk individuals within the community using human saliva as a medium, potentially leading to a simple, safe early warning system. METHODS: Saliva samples were collected from healthy controls (n=36) and HF patients (n=75). Salivary proteome profiles were analysed by Sequential Window Acquisition of All Theoretical fragment ion spectra - Mass Spectrometry (SWATH-MS)...
2017: Theranostics
https://www.readbyqxmd.com/read/29154550/biophysical-and-sequence-based-methods-for-identifying-monovalent-and-bivalent-antibodies-with-high-colloidal-stability
#4
Magfur E Alam, Steven B Geng, Christian Bender, Seth D Ludwig, Lars Linden, Rene Hoet, Peter M Tessier
In vitro antibody discovery and/or affinity maturation are often performed using antibody fragments (Fabs), but most monovalent Fabs are reformatted as bivalent IgGs (monoclonal antibodies, mAbs) for therapeutic applications. One problem related to reformatting antibodies is that the bivalency of mAbs can lead to increased antibody self-association and poor biophysical properties (e.g., reduced antibody solubility and increased viscosity). Therefore, it is important to identify monovalent Fabs early in the discovery and/or optimization process that will display favorable biophysical properties when reformatted as bivalent mAbs...
November 20, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29150397/fragment-based-design-synthesis-biological-evaluation-and-sar-of-1h-benzo-d-imidazol-2-yl-1h-indazol-derivatives-as-potent-pdk1-inhibitors
#5
Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L Warner, Sunil Sharma, David J Bearss, Hariprasad Vankayalapati
In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively...
October 28, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29143719/microbial-protein-targets-towards-understanding-and-intervention
#6
Paul W Denny
The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burdens caused by near untreatable microbial pathogens, there is an urgent need to identify new antimicrobials. Central to this is the elucidation of new, robustly validated, drug targets. Informed by industrial practice and concerns, the use of both biological and chemical tools in validation is key...
November 16, 2017: Parasitology
https://www.readbyqxmd.com/read/29118093/current-perspectives-in-fragment-based-lead-discovery-fbld
#7
REVIEW
Bas Lamoree, Roderick E Hubbard
It is over 20 years since the first fragment-based discovery projects were disclosed. The methods are now mature for most 'conventional' targets in drug discovery such as enzymes (kinases and proteases) but there has also been growing success on more challenging targets, such as disruption of protein-protein interactions. The main application is to identify tractable chemical startpoints that non-covalently modulate the activity of a biological molecule. In this essay, we overview current practice in the methods and discuss how they have had an impact in lead discovery - generating a large number of fragment-derived compounds that are in clinical trials and two medicines treating patients...
November 8, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29111727/bioisostere-identification-by-determining-the-amino-acid-binding-preferences-of-common-chemical-fragments
#8
Tomohiro Sato, Noriaki Hashimoto, Teruki Honma
To assist the structural optimization of hit/lead compound during drug discovery, various computational approaches to identify potentially useful bioisosteric conversions have been reported. Here, the preference of chemical fragments to hydrogen bond with specific amino acid residues was used to identify potential bioisosteric conversions. We first compiled a data set of chemical fragments frequently occurring in complex structures contained in Protein Data Bank. We then used a computational approach to determine the amino acids to which these chemical fragments most frequently hydrogen bonded...
November 7, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29111368/discovery-of-new-antimalarial-agents-second-generation-dual-inhibitors-against-fp-2-and-pfdhfr-via-fragments-assembely
#9
Wenhua Chen, Zhenghui Huang, Wanyan Wang, Fei Mao, Longfei Guan, Yun Tang, Hualiang Jiang, Jian Li, Jin Huang, Lubin Jiang, Jin Zhu
Malaria parasites are a leading cause of worldwide mortality from infectious disease. Cysteine protease falcipain-2 (FP-2) and Plasmodium falciparum dihydrofolate reductase (PfDHFR) play vital roles, which are absolutely essential, in the parasite life cycle. In this study, based on the structures of uniform fragments of reported PfDHFR inhibitors and the first-generation dual inhibitors against FP-2 and PfDHFR, we identified a novel series of dual inhibitors through fragments assembly. Lead optimization led to the discovery of 24, which showed high potency against FP-2 (IC50 = 10...
October 16, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29095571/generative-recurrent-networks-for-de-novo-drug-design
#10
Anvita Gupta, Alex T Müller, Berend J H Huisman, Jens A Fuchs, Petra Schneider, Gisbert Schneider
Generative artificial intelligence models present a fresh approach to chemogenomics and de novo drug design, as they provide researchers with the ability to narrow down their search of the chemical space and focus on regions of interest. We present a method for molecular de novo design that utilizes generative recurrent neural networks (RNN) containing long short-term memory (LSTM) cells. This computational model captured the syntax of molecular representation in terms of SMILES strings with close to perfect accuracy...
November 2, 2017: Molecular Informatics
https://www.readbyqxmd.com/read/29070410/exploring-natural-product-fragments-for-drug-and-probe-discovery
#11
Axel Pahl, Herbert Waldmann, Kamal Kumar
Fragment-based ligand discovery is a key technology to develop lead structures for drug discovery. The majority of the fragments employed so far is aromatic and sp2-configured, and there is a high demand of fragments with stereogenic centers. Natural products (NPs) are evolutionary selected ligands for a range of diverse macromolecular targets. Small-sized molecules - fragments - based on NPs may inherit the biological relevance of nature's treasure and could offer novel opportunities to engage challenging protein targets...
October 25, 2017: Chimia
https://www.readbyqxmd.com/read/28940929/allosteric-tuning-of-caspase-7-a-fragment-based-drug-discovery-approach
#12
Nicholas R Vance, Lokesh Gakhar, M Ashley Spies
The caspase family of cysteine proteases are highly sought-after drug targets owing to their essential roles in apoptosis, proliferation, and inflammation pathways. High-throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful approach for the discovery of innovative drug leads. This method has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors...
November 13, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28940386/customizable-de-novo-design-strategies-for-dock-application-to-hivgp41-and-other-therapeutic-targets
#13
William J Allen, Brian C Fochtman, Trent E Balius, Robert C Rizzo
De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement to virtual screening, from-scratch construction of molecules is not limited to compounds in pre-existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches and users can define very specific criteria in terms of properties or features to customize growth toward a particular region of chemical space...
November 15, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28929756/fragment-based-discovery-and-optimization-of-enzyme-inhibitors-by-docking-of-commercial-chemical-space
#14
Axel Rudling, Robert Gustafsson, Ingrid Almlöf, Evert Homan, Martin Scobie, Ulrika Warpman Berglund, Thomas Helleday, Pål Stenmark, Jens Carlsson
Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28929751/structural-biology-inspired-discovery-of-novel-kras-pde%C3%AE-inhibitors
#15
Yan Jiang, Chunlin Zhuang, Long Chen, Junjie Lu, Guoqiang Dong, Zhenyuan Miao, Wannian Zhang, Jian Li, Chunquan Sheng
Structural biology is a powerful tool for investigating the stereospecific interactions between a protein and its ligand. Herein, an unprecedented chiral binding pattern was observed for inhibitors of KRAS-PDEδ interactions. Virtual screening and X-ray crystallography studies revealed that two enantiomers of a racemic inhibitor could bind at different sites. Fragment-based drug design was used to identify highly potent PDEδ inhibitors that can be used as promising lead compounds for target validation and antitumor drug development...
October 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28920498/an-update-on-biomarker-discovery-and-use-in-axial-spondyloarthritis
#16
Walter P Maksymowych
Evaluation of diagnosis, disease activity, and risk for joint damage all represent important unmet clinical needs in the management of axial spondyloarthritis that have been explored using biomarkers. Areas covered: This review used the search terms biomarkers, ankylosing spondylitis, spondyloarthritis, spondyloarthropathy, pathogenesis, genetics, diagnostic tools, prognosis, to explore advances in biomarker development relevant to unmet clinical needs. Expert commentary: Despite major advances in the identification of genetic risk markers, HLA-B*27 remains the only marker with clinical utility for diagnostic purposes...
November 2017: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/28843566/partial-filling-affinity-capillary-electrophoresis-as-a-useful-tool-for-fragment-based-drug-discovery-a-proof-of-concept-on-thrombin
#17
E Farcaş, C Bouckaert, A-C Servais, J Hanson, L Pochet, M Fillet
With the emergence of more challenging targets, a relatively new approach, fragment-based drug discovery (FBDD), proved its efficacy and gained increasing importance in the pharmaceutical industry. FBDD identifies low molecular-weight (MW) ligands (fragments) that bind to biologically important macromolecules, then a structure-guided fragment growing or merging approach is performed, contributing to the quality of the lead. However, to select the appropriate fragment to be evolved, sensitive analytical screening methods must be used to measure the affinity in the μM or even mM range...
September 1, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28800229/fragment-based-drug-discovery-of-phosphodiesterase-inhibitors
#18
Fredrik Svensson, Andreas Bender, David Bailey
Phosphodiesterases are proving to be fruitful targets for drug discovery. At the same time fragment-based drug discovery has matured into a powerful and widely applied technique. In this communication we review the application of fragment-based drug discovery for the successful identification of novel 3',5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors, concentrating on both experimental and computational strategies for fragment screening and hit-to-lead development. To this end, we also mine the open access databases ChEMBL and PDB for fragments showing PDE inhibitory activity, as well as SureChEMBL for recent PDE related patents, to provide a wider context for exploring fragment diversity...
August 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28743961/fragment-optimization-for-gpcrs-by-molecular-dynamics-free-energy-calculations-probing-druggable-subpockets-of-the-a-2a-adenosine-receptor-binding-site
#19
Pierre Matricon, Anirudh Ranganathan, Eugene Warnick, Zhan-Guo Gao, Axel Rudling, Catia Lambertucci, Gabriella Marucci, Aitakin Ezzati, Mariama Jaiteh, Diego Dal Ben, Kenneth A Jacobson, Jens Carlsson
Fragment-based lead discovery is becoming an increasingly popular strategy for drug discovery. Fragment screening identifies weakly binding compounds that require optimization to become high-affinity leads. As design of leads from fragments is challenging, reliable computational methods to guide optimization would be invaluable. We evaluated using molecular dynamics simulations and the free energy perturbation method (MD/FEP) in fragment optimization for the A2A adenosine receptor, a pharmaceutically relevant G protein-coupled receptor...
July 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28715203/a-bioinorganic-approach-to-fragment-based-drug-discovery-targeting-metalloenzymes
#20
Seth M Cohen
Metal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign...
July 17, 2017: Accounts of Chemical Research
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