Identification of biologically active conformations in flexible drug molecules

Abstract

Small perturbations to the conformation of a flexible drug molecule due to substituent changes allow scope for exploring the effect of population shifts in the conformation without necessarily perturbing the basic mode of binding to the receptor. The correlation of the biological effect with a conformer fraction in a series of compounds may thus permit identification of the biologically active con former. A review of the difficulties in extracting such information from data on drug-receptor complexes is made. The phase environment of the drug-receptor complex, the effects of charge redistribution on binding due to strong charge interactions, and the possible poor alignment of bonds in a gross free-energy effect are considered in the development of a precise model for identifying the protonated form of a drug acting on a receptor in a nonaqueous phase. When counterions are employed to mimic the effects of charge reorganization on drug-receptor interaction, difficulties arise in relating the fraction of the relevant charged conformer in the nonaqueous phase to the reference aqueous concentration. It is shown that this problem can be circumvented by the use of conformer acidity constants which link the concentration of a protonated conformer to that of the unprotonated form. The advantage of their use lies in the similar entropies associated with protonation on surfaces of a given shape. Computation is greatly aided since for any given conformation the problem reduces to a single calculation involving the energetics of strong charge interaction, while the conformer statistics may be performed on the unprotonated molecule. The effect of a-methyl substitution on the flexible side chain of a phenoxypropanolamine molecule is used as an example of the potential use of the model.