- Water networks contribute to enthalpy/entropy compensation in protein-ligand binding
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The mechanism (or mechanisms) of enthalpy-entropy (H/S) compensation in protein-ligand binding remains controversial, and there are still no predictive models (theoretical or experimental) in which hypotheses of ligand binding can be readily tested. Here we describe a particularly well-defined system of protein and ligands - human carbonic anhydrase (HCA) and a series of benzothiazole sulfonamide ligands with different patterns of fluorination - that we use to define enthalpy/entropy (H/S) compensation in this system thermodynamically and structurally. The binding affinities of these ligands (with the exception of one ligand, in which the deviation is understood) to HCA are, despite differences in fluorination pattern, indistinguishable; they nonetheless reflect significant and compensating changes in enthalpy and entropy of binding. Analysis reveals that differences in the structure and thermodynamic properties of the waters surrounding the bound ligands are an important contributor to the observed H/S compensation. These results support the hypothesis that the molecules of water filling the active site of a protein, and surrounding the ligand, are as important as the contact interactions between the protein and the ligand for biomolecular recognition, and in determining the thermodynamics of binding.
- Breiten, Benjamin,Lockett, Matthew R.,Sherman, Woody,Fujita, Shuji,Al-Sayah, Mohammad,Lange, Heiko,Bowers, Carleen M.,Heroux, Annie,Krilov, Goran,Whitesides, George M.
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- Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels
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The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.
- Bertron, Jeanette L.,Gestwicki, Jason E.,Hayashi, Shigenari,Li, Xiaokai,Schwarz, Daniel M. C.,Shao, Hao,Tang, Benjamin C.
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- General Entry into o-,o′-Heteroatom-Linked N-(Hetero)aryl-Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar Cycloaddition
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A general redox-neutral approach into the o-,o′-heteroatom-linked N-(hetero)aryl-imidazole family of heteroaromatics has been developed. New types of heteroatom substituted carbimidoyl nitrenoids are efficiently realised from robust, bench-stable N-(heteroaryl)-pyridinium-N-aminides by formal gold-catalysed [3+2]-dipolar cycloadditions across ynamides. Broad structural variety and functional group tolerance allows rapid access into diverse functionalised scaffolds, as exemplified by the preparation of 8 different heteroaromatic cores. (Figure presented.).
- Garzón, Miguel,Arce, Elsa M.,Reddy, Raju Jannapu,Davies, Paul W.
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p. 1837 - 1843
(2017/06/09)
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- Analogues of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents
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The rhodacyanine, MKT-077, has antiproliferative activity against cancer cell lines through its ability to inhibit members of the heat shock protein 70 (Hsp70) family of molecular chaperones. However, MKT-077 is rapidly metabolized, which limits its use as either a chemical probe or potential therapeutic. We report the synthesis and characterization of MKT-077 analogues designed for greater stability. The most potent molecules, such as 30 (JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC50 values of 0.4 ± 0.03 and 0.7 ± 0.2 μM, respectively). The analogues modestly destabilized the chaperone clients, Akt1 and Raf1, and induced apoptosis in these cells. Further, the microsomal half-life of JG-98 was improved at least 7-fold (t1/2 = 37 min) compared to MKT-077 (t1/2 5 min). Finally, NMR titration experiments suggested that these analogues bind an allosteric site that is known to accommodate MKT-077. These studies advance MKT-077 analogues as chemical probes for studying Hsp70s roles in cancer.
- Li, Xiaokai,Srinivasan, Sharan R.,Connarn, Jamie,Ahmad, Atta,Young, Zapporah T.,Kabza, Adam M.,Zuiderweg, Erik. R. P.,Sun, Duxin,Gestwicki, Jason E.
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supporting information
p. 1042 - 1047
(2013/12/04)
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- Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain
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Current drugs for the treatment of seizure disorders, although effective in many patients, still suffer from a number of failures and are not effective in some forms of resistant epilepsies. Historically,many of these drugs have multiple mechanisms of action including calcium and sodium channel blockade as well as GABAergic activity and thus a number of associated side effects. Modulation of the M-current through opening ofKCNQ channels has been proposed as a way to attenuate neuroexcitability and have a therapeutic benefit for the treatment of seizure disorders. Therefore, as part of our program to identify new treatments for epilepsy, we set out to identify agonists of KCNQ channels. High throughput screening of our corporate collection led to the identification of 1, adamantane-1-carboxylic acid (3-methyl-3H-benzothiazol-2-ylidine) hydrazide, a potent KCNQ2/Q3 agonist. Herein, we describe the syntheses and structure - activity relationships of analogues of 1 as well as their in vivo activity in animal models of epilepsy and neuropathic pain. 2009 American Chemical Society.
- Fritch, Paul C.,McNaughton-Smith, Grant,Amato, George S.,Burns, James F.,Eargle, C. Wesley,Roeloffs, Rosemarie,Harrison, William,Jones, Leslie,Wickenden, Alan D.
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experimental part
p. 887 - 896
(2010/07/05)
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- New herbicidal fluorobenzothiazolyloxyacetamides
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Novel herbicidal fluorobenzothiazolyloxyacetamides of the formula STR1 in which R1 represents hydrogen or an optionally substituted radical from the group consisting of alkyl, alkenyl, alkinyl and aralkyl, R2 represents an optionally
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