A Quantitative Stereo‐Structure Activity Relationship Analysis of the Binding of Promiscuous Chiral Ligands to Different Receptors
P.A.F. Lehmann · Quantitative Structure-Activity Relationships · 1987
Abstract Many important compounds of pharmacological interest bind with high affinities to more than one receptor (promiscuous ligands). If in addition they are chiral, the stereoselectivity each receptor displays towards pairs of such stereoisomeric ligands is of theoretical and practical importance. The recent literature was culled for data sets in which affinity values were provided for both isomers of a stereoisomeric ligand at three or more receptors or receptor subtypes. Their multiple eudismic‐affinity analysis showed that in general stereoisomeric potency ratios increase as a function of affinity, thus validating an extension of Pfeiffer's Rule. The increase in stereoselectivity per unit increase in eutomer affinity (M.E.A.Q) tends towards 0.5 with most values lying between 0.3 and 0.7. A simple explanation is offered for this at the molecular level in which the M.E.A.Q. of 0.5 is interpreted in terms of the transfer of a methylene group from a lipidic to an aqueous environment. The implications for rational drug design and receptor speciation of this generalization are analyzed and it is suggested that quantitative stereo‐structure activity relationships (QSSAR) must be made an integral part of QSAR.