keyword
MENU ▼
Read by QxMD icon Read
search

Fragment Based Lead Discovery

keyword
https://www.readbyqxmd.com/read/28940929/allosteric-tuning-of-caspase-7-a-fragment-based-drug-discovery-approach
#1
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...
September 22, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28940386/customizable-de-novo-design-strategies-for-dock-application-to-hivgp41-and-other-therapeutic-targets
#2
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
#3
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
#4
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
#5
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...
September 22, 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
#6
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
#7
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28712745/the-ligand-binding-landscape-of-diacylglycerol-kinases
#10
Caroline E Franks, Sean T Campbell, Benjamin W Purow, Thurl E Harris, Ku-Lung Hsu
Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through ATP-dependent phosphorylation of the lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to study isoform-specific functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, ATP and small-molecule binding motifs of representative members from all five DGK subtypes...
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28712707/discovery-of-a-potent-angiotensin-converting-enzyme-inhibitor-via-virtual-screening
#11
Zhipeng Ke, Zhenzhen Su, Xinzhuang Zhang, Zeyu Cao, Yue Ding, Liang Cao, Gang Ding, Zhenzhong Wang, Haichun Liu, Wei Xiao
Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors...
August 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28693421/lipidmatch-an-automated-workflow-for-rule-based-lipid-identification-using-untargeted-high-resolution-tandem-mass-spectrometry-data
#12
Jeremy P Koelmel, Nicholas M Kroeger, Candice Z Ulmer, John A Bowden, Rainey E Patterson, Jason A Cochran, Christopher W W Beecher, Timothy J Garrett, Richard A Yost
BACKGROUND: Lipids are ubiquitous and serve numerous biological functions; thus lipids have been shown to have great potential as candidates for elucidating biomarkers and pathway perturbations associated with disease. Methods expanding coverage of the lipidome increase the likelihood of biomarker discovery and could lead to more comprehensive understanding of disease etiology. RESULTS: We introduce LipidMatch, an R-based tool for lipid identification for liquid chromatography tandem mass spectrometry workflows...
July 10, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28657441/molecular-modeling-studies-and-anti-tb-activity-of-trisubstituted-indolizine-analogues-molecular-docking-and-dynamic-inputs
#13
Mohammed A Khedr, Melendhran Pillay, Sandeep Chandrashekharappa, Deepak Chopra, Bandar E Aldhubiab, Mahesh Attimarad, Osama Ibrahim Alwassil, Koleka Mlisana, Bharti Odhav, Katharigatta N Venugopala
A series of trisubstituted indolizine analogues has been designed as a result of a fragment based approach to target the inhibition of mycobacterial enoyl-acyl carrier protein reductase. Anti-tuberculosis (TB) screening of the characterized compounds by a resazurin microplate assay method revealed that ethyl group at second position of indolizine nucleus exhibited activity against susceptible and multidrug-resistant strains of Mycobacterium tuberculosis at concentration of 5.5 μg/mL and 11.3 μg/mL, respectively...
June 28, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28648615/structural-biology-and-the-design-of-new-therapeutics-from-hiv-and-cancer-to-mycobacterial-infections-a-paper-dedicated-to-john-kendrew
#14
REVIEW
Sherine E Thomas, Vitor Mendes, So Yeon Kim, Sony Malhotra, Bernardo Ochoa-Montaño, Michal Blaszczyk, Tom L Blundell
Interest in applications of protein crystallography to medicine was evident, as the first high-resolution structures emerged in the 50s and 60s. In Cambridge, Max Perutz and John Kendrew sought to understand mutations in sickle cell and other genetic diseases related to hemoglobin, while in Oxford, the group of Dorothy Hodgkin became interested in long-lasting zinc-insulin crystals for treatment of diabetes and later considered insulin redesign, as synthetic insulins became possible. The use of protein crystallography in structure-guided drug discovery emerged as enzyme structures allowed the identification of potential inhibitor-binding sites and optimization of interactions of hits using the structure of the target protein...
August 18, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28619618/nmr-in-drug-design
#15
Mary J Harner, Luciano Mueller, Kevin J Robbins, Michael D Reily
The use of NMR as a tool to determine 3 dimensional protein solution structures, once a darling of the pharmaceutical industry, has largely given way to study of the interaction of prospective drugs with macromolecular targets. Many of these approaches involve ligand-centered studies, which have the advantage of speed and efficiency, but there are also many approaches that take directly from our learnings in macromolecular NMR and provide greater structural detail yet are still optimized for rapid turn-around of information...
August 15, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28560482/integrated-in-silico-fragment-based-drug-design-case-study-with-allosteric-modulators-on-metabotropic-glutamate-receptor-5
#16
Yuemin Bian, Zhiwei Feng, Peng Yang, Xiang-Qun Xie
GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases...
May 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28547936/fragment-based-drug-discovery-as-alternative-strategy-to-the-drug-development-for-neglected-diseases
#17
REVIEW
Juliana da Fonseca Rezende E Mello, Renan Augusto Gomes, Drielli Gomes Vital-Fujii, Glaucio Monteiro Ferreira, Gustavo Henrique Goulart Trossini
Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery (FBDD) emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area...
May 26, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28529704/towards-a-systems-approach-for-chronic-diseases-based-on-health-state-modeling
#18
Michael Rebhan
Rising pressure from chronic diseases means that we need to learn how to deal with challenges at a different level, including the use of systems approaches that better connect across fragments, such as disciplines, stakeholders, institutions, and technologies. By learning from progress in leading areas of health innovation (including oncology and AIDS), as well as complementary indications (Alzheimer's disease), I try to extract the most enabling innovation paradigms, and discuss their extension to additional areas of application within a systems approach...
2017: F1000Research
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
#19
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...
July 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28492317/discovery-of-a-potent-nonpeptidomimetic-small-molecule-antagonist-of-cellular-inhibitor-of-apoptosis-protein-1-ciap1-and-x-linked-inhibitor-of-apoptosis-protein-xiap
#20
Emiliano Tamanini, Ildiko M Buck, Gianni Chessari, Elisabetta Chiarparin, James E H Day, Martyn Frederickson, Charlotte M Griffiths-Jones, Keisha Hearn, Tom D Heightman, Aman Iqbal, Christopher N 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...
June 8, 2017: Journal of Medicinal Chemistry
keyword
keyword
89113
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"