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Fragment Based Lead Discovery

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https://www.readbyqxmd.com/read/28715203/a-bioinorganic-approach-to-fragment-based-drug-discovery-targeting-metalloenzymes
#1
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
#2
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
#3
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...
July 5, 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
#4
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
#5
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
#6
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 haemoglobin, 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 optimisation of interactions of hits using the structure of the target protein...
June 22, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28619618/nmr-in-drug-design
#7
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...
June 12, 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
#8
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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28475301/label-free-quantification-of-intracellular-mitochondrial-dynamics-using-dielectrophoresis
#13
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...
June 6, 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
#14
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
#15
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 Da) 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, which are highly abundant in crystal structures, are frequently ignored...
April 26, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28406299/discovery-and-optimization-of-isoquinoline-ethyl-ureas-as-antibacterial-agents
#16
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
#17
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
#18
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
#19
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
#20
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
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