Key to the pharmaceutical utility of certain macrocyclic drugs is a “chameleonic” ability to change their conformation to expose polar groups in aqueous solution, but bury them when traversing lipid membranes. Based on analysis of the structures of 20 macrocyclic compounds that are approved oral drugs, we propose that good solubility requires a topological polar surface area (TPSA, in Å2) of ≥0.2 × MW. Meanwhile, good passive membrane permeability requires a molecular (i.e. 3D) PSA in nonpolar environments of ≤140 Å2. We show that one or other of these limits is almost invariably violated for compounds with MW > 600 Da., suggesting that some degree of chameleonic behavior is required for most high MW oral drugs.
We discuss progress towards addressing three key questions pertaining to the design of screening libraries of synthetic non-peptidic macrocycles (MCs) for drug discovery: What structural and physicochemical properties of MCs maximize the likelihood of achieving strong and specific binding to protein targets? What features render a protein target suitable for binding MCs, and can this information be used to identify suitable targets for inhibition by MCs? What properties of synthetic MCs confer good pharmaceutical properties, and particularly good aqueous solubility coupled with passive membrane permeability? We additionally discuss how the criteria that define a meaningful MC screening hit are linked to the size of the screening library and the synthetic methodology employed in its preparation.
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