Interest of cluster significance analysis in structure-affinity relationships for non-xanthine heterocyclic antagonists of adenosine

• Published in: European journal of medicinal chemistry 1997-06, Vol.32 (6), p.493-504
• Main Authors: Adenot, M, Benezech, V, Bompart, J, Bonnet, P.A., Chapat, J.P., Grassy, G
• Format: Article
• Language: English
• Subjects: adenosine antagonist; AM1; Biological and medical sciences; cluster significance analysis; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; QSAR analysis; thermodynamics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(97)84012-3

In order to define some predictive rules for the discrimination of adenosine antagonists by their A 1-receptor affinity, we performed a systematic QSAR analysis. As no significant descriptors of affinity were found, we then proposed to introduce a calculated enthalpy or entropy change for the interaction as a first approximation of the affinity descriptors. Since the structural details of the common receptor binding site remain to be determined, we utilized an indirect strategy involving the simulation of amino acid residues that are thought to interact with the ligand. Estimating enthalpic and entropic components by means of a semi-empirical quantum mechanical AM1 force calculation, we found a significant clustering of enthalpy change values. This method provides a good descriptor of interaction and also a simple tool for testing hypotheses on the nature of putative binding sites.