4q30

Publication Abstract from PubMed

Understanding the thermodynamics of lead compound binding to a receptor can provide valuable information for drug design. The binding of compounds, particularly partial agonists, to subtypes of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor is, in some cases, driven by entropy increases. 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 enthalphic contribution to binding. Willardiines have uracil rings with pKA values ranging from 5.5 to 10. The binding of the charged form is largely enthalpy driven while that of the uncharged form is largely entropy driven. 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.

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. 2014 May 21. PMID:24850223^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.