154327-25-0Relevant articles and documents
Water networks contribute to enthalpy/entropy compensation in protein-ligand 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.
, p. 15579 - 15584 (2013)
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.
General Entry into o-,o′-Heteroatom-Linked N-(Hetero)aryl-Imidazole Motifs by Gold-Catalysed Formal [3+2]-Dipolar Cycloaddition
Garzón, Miguel,Arce, Elsa M.,Reddy, Raju Jannapu,Davies, Paul W.
, p. 1837 - 1843 (2017/06/09)
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.).
Novel KCNQ2/Q3 agonists as potential therapeutics for epilepsy and neuropathic pain
Fritch, Paul C.,McNaughton-Smith, Grant,Amato, George S.,Burns, James F.,Eargle, C. Wesley,Roeloffs, Rosemarie,Harrison, William,Jones, Leslie,Wickenden, Alan D.
experimental part, p. 887 - 896 (2010/07/05)
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.
