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Covalent inhibitors

Focco van den Akker, Robert A Bonomo
As a bacterial resistance strategy, serine β-lactamases have evolved from cell wall synthesizing enzymes known as penicillin-binding proteins (PBP), by not only covalently binding β-lactam antibiotics but, also acquiring mechanisms of deacylating these antibiotics. This critical deacylation step leads to release of hydrolyzed and inactivated β-lactams, thereby providing resistance for the bacteria against these antibiotics targeting the cell wall. To combat β-lactamase-mediated antibiotic resistance, numerous β-lactamase inhibitors were developed that utilize various strategies to inactivate the β-lactamase...
2018: Frontiers in Microbiology
Jiu-Yu Zhan, Ke Ma, Qing-Chuan Zheng, Guang-Hui Yang, Hong-Xing Zhang
Aldose reductase (AKR1B1) has been considered as a significant target for designing drugs to counteract the development of diabetic complications. In the present study, molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to make sure which tautomer is the preferred one among three tautomeric forms (Mtia1, Mtia2, and Mtia3) of 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (Mtia) for binding to AKR1B1. The overall structural features and the results of calculated binding free energies indicate that Mtia1 and Mtia2 have more superiority than Mtia3 in terms of binding to AKR1B1...
April 19, 2018: Journal of Biomolecular Structure & Dynamics
Anupama Tuladhar, Kathleen S Rein
The anticancer effect of manumycin A (Man A) has been attributed to the inhibition of farnesyl transferase (FTase), an enzyme that is responsible for post-translational modification of Ras proteins. However, we have discovered that Man A inhibits mammalian cytosolic thioredoxin reductase 1 (TrxR-1) in a time-dependent manner, with an IC50 of 272 nM with preincubation and 1586 nM without preincubation. The inhibition of TrxR-1 by Man A is irreversible and is the result of a covalent interaction between Man A and TrxR-1...
April 12, 2018: ACS Medicinal Chemistry Letters
Robert Wodtke, Christoph Hauser, Gloria Ruiz-Gomez, Elisabeth Jäckel, David Bauer, Martin Lohse, Alan Wong, Johanna Pufe, Friedrich-Alexander Ludwig, Steffen Fischer, Sandra Hauser, Dieter Greif, Maria Teresa Pisabarro, Jens Pietzsch, Markus Pietsch, Reik Löser
Transglutaminase 2 (TGase 2)-catalysed transamidation represents an important posttranslational mechanism for protein modification with implications in physiological and pathophysiological conditions including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis and therapy of these diseases. In this study, we report on the synthesis and kinetic characterisation of Nε -acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography...
April 17, 2018: Journal of Medicinal Chemistry
Jeffy Chern, Chun-Ping Lu, Zhanxiong Fang, Ching-Ming Chang, Kuo-Feng Hua, Yi-Ting Chen, Cheng Yang Ng, Yi-Lin Sophia Chen, Yulin Lam, Shih-Hsiung Wu
Traditional medicines provide a fertile ground to explore potent lead compounds; yet, their transformation into modern drugs is fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. Herein we revealed Z-(+)-isochaihulactone 1 exhibited significant inhibition against MDR cancer cell lines and mice xenografts. By NMR spectroscopy, 1 was shown to resist to an off-targeting thiolate, thus giving 1 a target covalent inhibitor-like (TCI) property. By identifying the pharmacophore of 1 (α,β-unsaturated moiety), a 1-derived probe was designed and synthesized for TCI-oriented activity-based proteome profiling (TCI-ABPP)...
April 17, 2018: Angewandte Chemie
Xiaochen Hou, Meining Wang, Yi Wen, Tengfeng Ni, Xiangna Guan, Lefu Lan, Naixia Zhang, Ao Zhang, Cai-Guang Yang
Sortase A (SrtA) anchors surface proteins to the cell wall and aids biofilm formation during infection, which functions as a key virulence factor of important Gram-positive pathogens, such as Staphylococcus aureus. At present researchers need a way in which to validate whether or not SrtA is a druggable target alternative to the conventional antibiotic targets in the mechanism. In this study, we performed a high-throughput screening and identified a new class of potential inhibitors of S. aureus SrtA, which are derived from natural products and contain the quinone skeleton...
April 4, 2018: Bioorganic & Medicinal Chemistry Letters
Jean-Francois Fournier, Laurence Clary, Sandrine Chambon, Laurence Dumais, Craig Steven Harris, Corinne Millois-Barbuis, Romain Pierre, Sandrine Talano, Etienne Thoreau, Jérome Aubert, Michèle Aurelly, Claire Bouix-Peter, Anne Brethon, Laurent Chantalat, Olivier Christin, Catherine Comino, Ghizlane El-Bazbouz, Anne-Laurence Ghilini, Tatiana Isabet, Claude Lardy, Anne-Pascale Luzy, Céline Mathieu, Kenny Mebrouk, Danielle Orfila, Jonathan Pascau, Kevin Reverse, Didier Roche, Vincent Rodeschini, Laurent François Hennequin
The use of an interleukin beta antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1β into active IL-1β, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases...
April 12, 2018: Journal of Medicinal Chemistry
Dominic G Hoch, Daniel Abegg, Alexander Adibekian
Proteomic profiling using bioorthogonal chemical probes that selectively react with certain amino acids is now a widely used method in life sciences to investigate enzymatic activities, study posttranslational modifications and discover novel covalent inhibitors. Over the past two decades, researchers have developed selective probes for several different amino acids, including lysine, serine, cysteine, threonine, tyrosine, aspartate and glutamate. Among these amino acids, cysteines are particularly interesting due to their highly diverse and complex biochemical role in our cells...
April 12, 2018: Chemical Communications: Chem Comm
Lyn H Jones
The reaction of small molecule chemical probes with proteins has been harnessed to develop covalent inhibitor drugs and protein profiling technologies. This Essay discusses some of the recent enhancements to the chemical biology toolkit that are enabling the study of previously unchartered areas of chemoproteomic space. An analysis of the kinome is used to illustrate the potential for these approaches to pursue new targets using reactive chemical probes.
April 12, 2018: Angewandte Chemie
Kyla A L Collins, Timothy J Stuhlmiller, Jon S Zawistowski, Michael P East, Trang T Pham, Claire R Hall, Daniel R Goulet, Samantha M Bevill, Steven P Angus, Sara H Velarde, Noah Sciaky, Tudor I Oprea, Lee M Graves, Gary L Johnson, Shawn M Gomez
Multiplexed small molecule inhibitors covalently bound to Sepharose beads (MIBs) were used to capture functional kinases in luminal, HER2-enriched and triple negative (basal-like and claudin-low) breast cancer cell lines and tumors. Kinase MIB-binding profiles at baseline without perturbation proteomically distinguished the four breast cancer subtypes. Understudied kinases, whose disease associations and pharmacology are generally unexplored, were highly represented in MIB-binding taxonomies and are integrated into signaling subnetworks with kinases that have been previously well characterized in breast cancer...
March 20, 2018: Oncotarget
Shama Khan, Imane Bjij, Robin M Betz, Mahmoud Es Soliman
AIM: Irreversible covalent drug inhibition is an emerging paradigm; however, critical gaps in unraveling the efficacy of molecular determinants still persist. METHODOLOGY: We compare two ERK2 inhibitors with different binding modes. A 5-7-Oxozeaenol is selective inhibitor which irreversibly binds ERK2 by the formation of covalent bond with Cys166 while 5-iodotubercidin binds noncovalently. Result & discussion: Covalent inhibition showed greater protein stability, favorable binding energetics (irreversible inhibition binding free energy [ΔGbind ] = -40...
April 9, 2018: Future Medicinal Chemistry
Florian B Zauner, Brigitta Elsasser, Elfriede Dall, Chiara Cabrele, Hans Brandstetter
Legumain is a dual-function protease peptide ligase whose activities are of great interest to researchers studying plant physiology and to biotechnological applications. However, the molecular mechanisms determining the specificities for proteolysis and ligation are unclear because structural information on the substrate recognition by a fully activated plant legumain is unavailable. Here, we present the X-ray structure of Arabidopsis thaliana legumain isoform γ (AtLEGγ) in complex with the covalent peptidic Ac-YVAD chloro methyl ketone (CMK) inhibitor targeting the catalytic cysteine...
April 8, 2018: Journal of Biological Chemistry
Harun Patel, Rahul Pawara, Sanjay Surana
The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are generally utilized as a part of patients with non-small cell lung carcinoma (NSCLC). However, EGFR T790M mutation results in resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation has been in active clinical development to triumph the resistance problem; they covalently bind with conserved Cys797 inside the EGFR active site, offering both potency and kinase-selectivity. Third generation drugs target C797, which makes the C797S resistance mutation more subtle...
March 29, 2018: Computational Biology and Chemistry
Zhijian Li, Qingxi Min, Haoji Huang, Ruixuan Liu, Yongyan Zhu, Quanhong Zhu
A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 μM and 0.86 μM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry...
March 29, 2018: Bioorganic & Medicinal Chemistry Letters
Richard Lonsdale, Richard A Ward
Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target...
April 5, 2018: Chemical Society Reviews
Maria Qatato, Joanna Szumska, Vladislav Skripnik, Eddy Rijntjes, Josef Köhrle, Klaudia Brix
Trace amine-associated receptor 1 (Taar1) has been suggested as putative receptor of thyronamines. These are aminergic messengers with potential metabolic and neurological effects countering their contingent precursors, the thyroid hormones (THs). Recently, we found Taar1 to be localized at the primary cilia of rodent thyroid epithelial cells in vitro and in situ . Thus, Taar1 is present in a location of thyroid follicles where it might be involved in regulation of cathepsin-mediated proteolytic processing of thyroglobulin, and consequently TH synthesis...
2018: Frontiers in Pharmacology
Masahiro Takeyama, Keiji Nogami, Kana Sasai, Shoko Furukawa, Midori Shima
The link between factor (F)VIII and FX is essential for optimum activity of the tenase complex. The interactive site(s) in FVIII for FX remains to be completely clarified, however. We investigated the FVIII A2 domain-FX association that was speculated from inhibitory mechanism(s) by an anti-A2 autoantibody. SDS-PAGE demonstrated that the purified inhibitor IgG recognizing residues 373-562 blocked FXa cleavage at Arg372 in FVIII, and surface-plasmon resonance (SPR)-based assays showed that intact A2 subunit directly bound to FX ( K d ; 63 nM)...
April 3, 2018: Thrombosis and Haemostasis
Yosuke Masuda, Tomoki Yoshida, Noriyuki Yamaotsu, Shuichi Hirono
We recently reported that the Gibbs free energy of hydrolytic water molecules (ΔGwat ) in acyl-trypsin intermediates calculated by hydration thermodynamics analysis could be a useful metric for estimating the catalytic rate constants (kcat ) of mechanism-based reversible covalent inhibitors. For thorough evaluation, the proposed method was tested with an increased number of covalent ligands that have no corresponding crystal structures. After modeling acyl-trypsin intermediate structures using flexible molecular superposition, ΔGwat values were calculated according to the proposed method...
2018: Chemical & Pharmaceutical Bulletin
Benjamin R Huebner, Ernest E Moore, Hunter B Moore, Eduardo Gonzalez, Marguerite R Kelher, Angela Sauaia, Anirban Banerjee, Christopher C Silliman
BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of the fibrinolytic system, covalently binding to tissue plasminogen activator and blocking its activity. Fibrinolysis shutdown is evident in the majority of severely injured patients in the first 24 h and is thought to be due to PAI-1. The source of this PAI-1 is thought to be predominantly endothelial cells, but there are known organ-specific differences, with higher levels thought to be in the liver. Thrombin generation is also elevated in injured patients and is a potent stimulus for PAI-1 release in human umbilical endothelial cells...
May 2018: Journal of Surgical Research
Yong Xu, Jon Cuccui, Carmen Denman, Tripty Maharjan, Brendan W Wren, Gerd K Wagner
Lipooligosaccharide (LOS) structures in the outer core of Gram-negative mucosal pathogens such as Neisseria meningitidis and Haemophilus influenzae contain characteristic glycoepitopes that contribute significantly to bacterial virulence. An important example is the digalactoside epitope generated by the retaining α-1,4-galactosyltransferase LgtC. These digalactosides camouflage the pathogen from the host immune system and increase its serum resistance. Small molecular inhibitors of LgtC are therefore sought after as chemical tools to study bacterial virulence, and as potential candidates for anti-virulence drug discovery...
March 6, 2018: Bioorganic & Medicinal Chemistry
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