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ITC drug discovery

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https://www.readbyqxmd.com/read/28986384/mass-spectrometry-for-fragment-screening
#1
REVIEW
Daniel Shiu-Hin Chan, Andrew J Whitehouse, Anthony G Coyne, Chris Abell
Fragment-based approaches in chemical biology and drug discovery have been widely adopted worldwide in both academia and industry. Fragment hits tend to interact weakly with their targets, necessitating the use of sensitive biophysical techniques to detect their binding. Common fragment screening techniques include differential scanning fluorimetry (DSF) and ligand-observed NMR. Validation and characterization of hits is usually performed using a combination of protein-observed NMR, isothermal titration calorimetry (ITC) and X-ray crystallography...
October 6, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/28926243/are-we-there-yet-applying-thermodynamic-and-kinetic-profiling-on-embryonic-ectoderm-development-eed-hit-to-lead-program
#2
Ying Wang, Rohinton P Edalji, Sanjay C Panchal, Chaohong Sun, Stevan W Djuric, Anil Vasudevan
It is advocated that kinetic and thermodynamic profiling of bioactive compounds should be incorporated and utilized as complementary tools for hit and lead optimizations in drug discovery. To assess their applications in the EED hit-to-lead optimization process, large amount of thermodynamic and kinetic data were collected and analyzed via isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. Slower dissociation rates (koff) of the lead compounds were observed as the program progressed...
October 5, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28835636/potential-inhibitors-designed-against-ndm-1-type-metallo-%C3%AE-lactamases-an-attempt-to-enhance-efficacies-of-antibiotics-against-multi-drug-resistant-bacteria
#3
Asad U Khan, Abid Ali, Danishuddin, Gaurava Srivastava, Ashok Sharma
NDM-1 and its variants are the most prevalent types of metallo-β-lactamases, hydrolyze almost all antibiotics of β-lactam group leading to multiple-drug resistance in bacteria. No inhibitor has yet been obtained for NDM-1 or other class of metallo-β-lactamases. Therefore, strategies to identify novel anti-β-lactamase agents with specific mechanisms of action are the need of an hour. In this study, we have reported the discovery of novel non-β-lactam inhibitors against NDM-1 by multi-step virtual screening approach...
August 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28696692/evaluating-force-field-performance-in-thermodynamic-calculations-of-cyclodextrin-host-guest-binding-water-models-partial-charges-and-host-force-field-parameters
#4
Niel M Henriksen, Michael K Gilson
Computational prediction of noncovalent binding free energies with methods based on molecular mechanical force fields has become increasingly routine in drug discovery projects, where they promise to speed the discovery of small molecule ligands to bind targeted proteins with high affinity. Because the reliability of free energy methods still has significant room for improvement, new force fields, or modifications of existing ones, are regularly introduced with the aim of improving the accuracy of molecular simulations...
September 12, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28574264/synergetic-determination-of-thermodynamic-and-kinetic-signatures-using-isothermal-titration-calorimetry-a-full-curve-fitting-approach
#5
Dexing Li, Lan Chen, Ruimin Wang, Renxiao Liu, Guanglu Ge
Thermodynamic and kinetic signatures are pivotal information for revealing the binding mechanisms of biomolecules, and they play an indispensable role in drug discovery and optimization. While noncalorimetric methods measure only a part of these signatures, isothermal titration calorimetry (ITC) is considered to have the potential to acquire full signatures in an experiment. However, kinetic parameters are generally difficult to extract from ITC curves, as they are inevitably affected by the instrument-response function and the collateral heat of associated process during titrations...
June 14, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28470298/fluorescence-enhancement-and-pka-shift-of-a-rho-kinase-inhibitor-by-a-synthetic-receptor
#6
Hang Yin, Linmin Chen, Binrui Yang, David Bardelang, Chunming Wang, Simon M Y Lee, Ruibing Wang
Fasudil (FSD), a selective rho kinase (ROCK) inhibitor, was found to form 1 : 1 host-guest inclusion complexes with a synthetic macrocyclic receptor, cucurbit[7]uril (CB[7]), in aqueous solutions, as evidenced by (1)H NMR, photoluminescence and UV-visible spectroscopic titrations, isothermal titration calorimetry (ITC) titration, and electrospray ionization (ESI) mass spectrometry, as well as density functional theory (DFT) molecular modeling. Upon encapsulation, whereas the UV-vis absorbance of FSD experienced a moderate decrease and bathochromic shift, the fluorescence intensity of FSD at 354 nm was dramatically enhanced for up to 69-fold at neutral pH, which could potentially be applied in fluorescent tracking of the drug delivery and release...
May 23, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27564259/validating-and-enabling-phosphoglycerate-dehydrogenase-phgdh-as-a-target-for-fragment-based-drug-discovery-in-phgdh-amplified-breast-cancer
#7
Judith E Unterlass, Arnaud Baslé, Timothy J Blackburn, Julie Tucker, Céline Cano, Martin E M Noble, Nicola J Curtin
3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in PHGDH-amplified breast cancer. Knockdown caused reduced proliferation in the PHGDH-amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected...
August 22, 2016: Oncotarget
https://www.readbyqxmd.com/read/27139825/structures-of-endothiapepsin-fragment-complexes-from-crystallographic-fragment-screening-using-a-novel-diverse-and-affordable-96-compound-fragment-library
#8
Franziska U Huschmann, Janina Linnik, Karine Sparta, Monika Ühlein, Xiaojie Wang, Alexander Metz, Johannes Schiebel, Andreas Heine, Gerhard Klebe, Manfred S Weiss, Uwe Mueller
Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds...
May 2016: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/26794356/isothermal-titration-calorimetry-to-characterize-enzymatic-reactions
#9
Luca Mazzei, Stefano Ciurli, Barbara Zambelli
Isothermal titration calorimetry (ITC) is a technique that measures the heat released or absorbed during a chemical reaction as an intrinsic probe to characterize any chemical process that involves heat changes spontaneously occurring during the reaction. The general features of this method to determine the kinetic and thermodynamic parameters of enzymatic reactions (kcat, KM, ΔH) are described and discussed here together with some detailed applications to specific cases. ITC does not require any modification or labeling of the system under analysis, can be performed in solution, and needs only small amounts of enzyme...
2016: Methods in Enzymology
https://www.readbyqxmd.com/read/26530431/binding-thermodynamics-of-paromomycin-neomycin-neomycin-dinucleotide-and-dipna-conjugates-to-bacterial-and-human-rrna
#10
COMPARATIVE STUDY
Javier Alguacil, Jordi Robles, Clara Ràfols, Elisabeth Bosch
Isothermal titration calorimetry (ITC) is a powerful technique able to evaluate the energetics of target-drug binding within the context of drug discovery. In this work, the interactions of RNAs reproducing bacterial and human ribosomal A-site, with two well-known antibiotic aminoglycosides, Paromomycin and Neomycin, as well as several Neomycin-dinucleotide and -diPNA conjugates, have been evaluated by ITC and the corresponding thermodynamic quantities determined. The comparison of the thermodynamic data of aminoglycosides and their chemical analogues allowed to select Neomycin-diPNA conjugates as the best candidates for antimicrobial activity...
April 2016: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/26524379/first-in-class-inhibitors-of-sulfur-metabolism-with-bactericidal-activity-against-non-replicating-m-tuberculosis
#11
Prakash B Palde, Ashima Bhaskar, Laura E Pedró Rosa, Franck Madoux, Peter Chase, Vinayak Gupta, Timothy Spicer, Louis Scampavia, Amit Singh, Kate S Carroll
Development of effective therapies to eradicate persistent, slowly replicating M. tuberculosis (Mtb) represents a significant challenge to controlling the global TB epidemic. To develop such therapies, it is imperative to translate information from metabolome and proteome adaptations of persistent Mtb into the drug discovery screening platforms. To this end, reductive sulfur metabolism is genetically and pharmacologically implicated in survival, pathogenesis, and redox homeostasis of persistent Mtb. Therefore, inhibitors of this pathway are expected to serve as powerful tools in its preclinical and clinical validation as a therapeutic target for eradicating persisters...
January 15, 2016: ACS Chemical Biology
https://www.readbyqxmd.com/read/26505788/enzyme-kinetics-and-inhibition-of-histone-acetyltransferase-kat8
#12
Hannah Wapenaar, Petra E van der Wouden, Matthew R Groves, Dante Rotili, Antonello Mai, Frank J Dekker
Lysine acetyltransferase 8 (KAT8) is a histone acetyltransferase (HAT) responsible for acetylating lysine 16 on histone H4 (H4K16) and plays a role in cell cycle progression as well as acetylation of the tumor suppressor protein p53. Further studies on its biological function and drug discovery initiatives will benefit from the development of small molecule inhibitors for this enzyme. As a first step towards this aim we investigated the enzyme kinetics of this bi-substrate enzyme. The kinetic experiments indicate a ping-pong mechanism in which the enzyme binds Ac-CoA first, followed by binding of the histone substrate...
November 13, 2015: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26320641/multiple-ligand-detection-and-affinity-measurement-by-ultrafiltration-and-mass-spectrometry-analysis-applied-to-fragment-mixture-screening
#13
Shanshan Qin, Yiran Ren, Xu Fu, Jie Shen, Xin Chen, Quan Wang, Xin Bi, Wenjing Liu, Lixin Li, Guangxin Liang, Cheng Yang, Wenqing Shui
Binding affinity of a small molecule drug candidate to a therapeutically relevant biomolecular target is regarded the first determinant of the candidate's efficacy. Although the ultrafiltration-LC/MS (UF-LC/MS) assay enables efficient ligand discovery for a specific target from a mixed pool of compounds, most previous analysis allowed for relative affinity ranking of different ligands. Moreover, the reliability of affinity measurement for multiple ligands with UF-LC/MS has hardly been strictly evaluated. In this study, we examined the accuracy of K(d) determination through UF-LC/MS by comparison with classical ITC measurement...
July 30, 2015: Analytica Chimica Acta
https://www.readbyqxmd.com/read/26078037/structure-based-design-of-diverse-inhibitors-of-mycobacterium-tuberculosis-n-acetylglucosamine-1-phosphate-uridyltransferase-combined-molecular-docking-dynamic-simulation-and-biological-activity
#14
Vijay Soni, Priyanka Suryadevara, Dharmarajan Sriram, Santhosh Kumar, Vinay Kumar Nandicoori, Perumal Yogeeswari
Persistent nature of Mycobacterium tuberculosis is one of the major factors which make the drug development process monotonous against this organism. The highly lipophilic cell wall, which constituting outer mycolic acid and inner peptidoglycan layers, acts as a barrier for the drugs to enter the bacteria. The rigidity of the cell wall is imparted by the peptidoglycan layer, which is covalently linked to mycolic acid by arabinogalactan. Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) serves as the starting material in the biosynthesis of this peptidoglycan layers...
July 2015: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/25978964/identification-of-indole-inhibitors-of-human-hematopoietic-prostaglandin-d2-synthase-hh-pgds
#15
Fredrik Edfeldt, Johan Evenäs, Matti Lepistö, Alison Ward, Jens Petersen, Lisa Wissler, Mattias Rohman, Ulf Sivars, Karin Svensson, Matthew Perry, Isabella Feierberg, Xiao-Hong Zhou, Thomas Hansson, Frank Narjes
Human H-PGDS has shown promise as a potential target for anti-allergic and anti-inflammatory drugs. Here we describe the discovery of a novel class of indole inhibitors, identified through focused screening of 42,000 compounds and evaluated using a series of hit validation assays that included fluorescence polarization binding, 1D NMR, ITC and chromogenic enzymatic assays. Compounds with low nanomolar potency, favorable physico-chemical properties and inhibitory activity in human mast cells have been identified...
June 15, 2015: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/25600407/reversible-and-irreversible-small-molecule-inhibitors-of-monoamine-oxidase-b-mao-b-investigated-by-biophysical-techniques
#16
Rafael J Rojas, Dale E Edmondson, Terri Almos, Roderick Scott, Mark E Massari
Monoamine oxidase B (MAO-B) plays a key role in the metabolism of dopamine, a neurotransmitter critical for the maintenance of cognitive function. Consequently, MAO-B is an important therapeutic target for disorders characterized by a decline in dopaminergic neurotransmission, including Parkinson's disease (PD). An emerging strategy in drug discovery is to utilize the biophysical approaches of thermal shift and isothermal titration calorimetry (ITC) to gain insight into binding modality and identify thermodynamically privileged chemical scaffolds...
February 15, 2015: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/25384157/discovery-of-am-7209-a-potent-and-selective-4-amidobenzoic-acid-inhibitor-of-the-mdm2-p53-interaction
#17
Yosup Rew, Daqing Sun, Xuelei Yan, Hilary P Beck, Jude Canon, Ada Chen, Jason Duquette, John Eksterowicz, Brian M Fox, Jiasheng Fu, Ana Z Gonzalez, Jonathan Houze, Xin Huang, Min Jiang, Lixia Jin, Yihong Li, Zhihong Li, Yun Ling, Mei-Chu Lo, Alexander M Long, Lawrence R McGee, Joel McIntosh, Jonathan D Oliner, Tao Osgood, Anne Y Saiki, Paul Shaffer, Yu Chung Wang, Sarah Wortman, Peter Yakowec, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Julio C Medina, Steven H Olson
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2...
December 26, 2014: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/25181397/spectroscopic-and-thermodynamic-insights-into-the-interaction-between-proflavine-and-human-telomeric-g-quadruplex-dna
#18
Vivek Kumar, Abhigyan Sengupta, Krishna Gavvala, Raj Kumar Koninti, Partha Hazra
The G-quadruplex (GQ-DNA), an alternative structure motif of DNA, has emerged as a novel and exciting target for anticancer drug discovery. GQ-DNA formed in the presence of monovalent cations (Na(+)/K(+)) by human telomeric DNA is a point of interest due to their direct relevance for cellular aging and abnormal cell growths. Small molecules that selectively target and stabilize G-quadruplex structures are considered to be potential therapeutic anticancer agents. Herein, we probe G-quadruplex and proflavine (a well-known DNA intercalator, hence acting as an anticarcinogen) association through steady state and time-resolved fluorescence spectroscopy to explore the effect of stabilization of GQ-DNA by this well-known DNA intercalator...
September 25, 2014: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/25081642/the-use-of-nanopore-analysis-for-discovering-drugs-which-bind-to-%C3%AE-synuclein-for-treatment-of-parkinson-s-disease
#19
Omid Tavassoly, Joe Kakish, Sergiy Nokhrin, Oleg Dmitriev, Jeremy S Lee
A major feature of Parkinson's disease is the formation of Lewy bodies in dopaminergic neurons which consist of misfolded α-synuclein. The binding of natural products to α-synuclein was evaluated by nanopore analysis and caffeine, curcumin, and nicotine all caused large conformational changes which may be related to their known neuroprotective effect in Parkinson's disease. The binding of the stereoisomers of nicotine were also studied by ITC, CD and NMR. It is proposed that (-)-nicotine causes the folding of α-synuclein into a loop with interaction between the N- and C-termini...
December 17, 2014: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/24747990/hot-biological-catalysis-isothermal-titration-calorimetry-to-characterize-enzymatic-reactions
#20
Luca Mazzei, Stefano Ciurli, Barbara Zambelli
Isothermal titration calorimetry (ITC) is a well-described technique that measures the heat released or absorbed during a chemical reaction, using it as an intrinsic probe to characterize virtually every chemical process. Nowadays, this technique is extensively applied to determine thermodynamic parameters of biomolecular binding equilibria. In addition, ITC has been demonstrated to be able of directly measuring kinetics and thermodynamic parameters (kcat, KM, ΔH) of enzymatic reactions, even though this application is still underexploited...
2014: Journal of Visualized Experiments: JoVE
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