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Thermodynamics and mechanism of the interaction of willardiine partial agonists with a glutamate receptor: implications for drug development.

Martinez M, Ahmed AH, Loh AP, Oswald RE
Biochemistry 53 3790-5 (2014)
Cited: 5 times
EuropePMC logo PMID: 24850223

Abstract

Understanding the thermodynamics of binding of a lead compound to a receptor can provide valuable information for drug design. The binding of compounds, particularly partial agonists, to subtypes of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor is, in some cases, driven by increases in entropy. Using a series of partial agonists based on the structure of the natural product, willardiine, we show that the charged state of the ligand determines the enthalpic contribution to binding. Willardiines have uracil rings with pKa values ranging from 5.5 to 10. The binding of the charged form is largely driven by enthalpy, while that of the uncharged form is largely driven by entropy. This is due at least in part to changes in the hydrogen bonding network within the binding site involving one water molecule. This work illustrates the importance of charge to the thermodynamics of binding of agonists and antagonists to AMPA receptors and provides clues for further drug discovery.

Articles - 4q30 mentioned but not cited (1)

  1. Thermodynamics and mechanism of the interaction of willardiine partial agonists with a glutamate receptor: implications for drug development. Martinez M, Ahmed AH, Loh AP, Oswald RE. Biochemistry 53 3790-3795 (2014)


Reviews citing this publication (1)

  1. Willardiine and Its Synthetic Analogues: Biological Aspects and Implications in Peptide Chemistry of This Nucleobase Amino Acid. Palumbo R, Omodei D, Vicidomini C, Roviello GN, Roviello GN. Pharmaceuticals (Basel) 15 1243 (2022)

Articles citing this publication (3)

  1. Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors. Kristensen AS, Hansen KB, Naur P, Olsen L, Kurtkaya NL, Dravid SM, Kvist T, Yi F, Pøhlsgaard J, Clausen RP, Gajhede M, Kastrup JS, Traynelis SF. Mol Pharmacol 89 253-262 (2016)
  2. A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors. Lima Neto JX, Fulco UL, Albuquerque EL, Corso G, Bezerra EM, Caetano EW, da Costa RF, Freire VN. Phys Chem Chem Phys 17 13092-13103 (2015)
  3. Synthesis of new unnatural N(α)-Fmoc pyrimidin-4-one amino acids: use of the p-benzyloxybenzyloxy group as a pyrimidinone masking group. ElMarrouni A, Heras M. Org Biomol Chem 13 851-858 (2015)


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