Unmasking Conformationally Adaptable Lipids as Drug Receptors

This perspective presents evidence that conformationally adaptable lipids that readily conform to the shape of neighboring molecules, can act as receptors for lipophilic drugs. Specifically, Nearest-Neighbor Recognition (NNR) measurements indicate that chloroform, halothane, and isoflurane form 1:1 complexes with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) in cholesterol-rich membrane leaflets. Biochemical studies of the effects of 63 amphipathic molecules on human red blood cells have shown strikingly similar results. A "wrap-around" model is proposed to account for these findings, where conformationally adaptable lipids outcompete cholesterol for binding to the lipophilic agent. Raman spectroscopic analyses support this model by revealing increased gauche conformations in the hydrocarbon chains of DPPC upon complexation with chloroform. More broadly, it is expected that consideration of conformationally adaptable lipids as additional receptors will enhance the design and optimization of many lipophilic drugs.