The cellular membrane as a mediator for small molecule interaction with membrane proteins

Abstract

The cellular membrane constitutes the first element that encounters a wide variety of molecular species to which a cell might be exposed. Hosting a large number of structurally and functionally diverse proteins associated with this key metabolic compartment, the membrane not only directly controls the traffic of various molecules in and out of the cell, it also participates in such diverse and important processes as signal transduction and chemical processing of incoming molecular species. In this article, we present a number of cases where details of interaction of small molecular species such as drugs with the membrane, which are often experimentally inaccessible, have been studied using advanced molecular simulation techniques. We have selected systems in which partitioning of the small molecule with the membrane constitutes a key step for its final biological function, often binding to and interacting with a protein associated with the membrane. These examples demonstrate that membrane partitioning is not only important for the overall distribution of drugs and other small molecules into different compartments of the body, it may also play a key role in determining the efficiency and the mode of interaction of the drug with its target protein.

Ensartinib (X-396) Effectively Modulates Pharmacokinetic Resistance Mediated by ABCB1 and ABCG2 Drug Efflux Transporters and CYP3A4 Biotransformation Enzyme

“…Although the CYP3A4 interaction was confirmed by a molecular docking simulation, the effect of ensartinib on this enzyme in cellular model systems was comparatively modest. This is unsurprising because the intracellular activities of ligands are known to be limited by factors such as their capacity for membrane penetration, their distribution and transport by efflux transporters or enzymes, trapping in endosomes, cytotoxicity, and so on [33]. Importantly, because ABCB1, ABCG2, CYP3A4, and CYP2C9 interacted with ensartinib at concentrations that may occur in the plasma of oncological patients (Cmax = 1 µM) [30], these transporters and enzymes are potential perpetrators of clinically relevant DDIs.…”

Lipid membranes: Theory and simulations bridged to experiments

“…Pasenkiewicz-Gierula et al also provide a concrete example of polymyxin B that is one of antimicrobial compounds interacting with lipid headgroups. This discussion is extended in the paper by Mayne et al [4], which presents an overview of the behavior of anesthetics, drugs, and hormones at the interfacial region of membranes.…”

“…Casciola and Tarek in turn concentrate in particular on pores formed by an electric field, and how the pores are involved in the transfer of siRNA [3]. Another important process dealing with permeation of gases through lipid bilayers is discussed in detail in the article by Mayne et al [4].…”

A Perspective: Active Role of Lipids in Neurotransmitter Dynamics

“…It is well established that hydrophobic (Bwater-hating^) small molecules can bind on the cell membrane and, then, diffuse along its plane towards their membrane-embedded receptors (Fig. 1a) [39][40][41]. Accordingly, it comes to reason that the membrane has another integral and direct function in the synaptic neurotransmission that should not be overlooked; i.e., the NTs are either attracted (lipophilic) to or repelled (lipophobic) by the outer leaflet surface of the postsynaptic cell membrane [42].…”

“…This is not surprising considering that charge separation in CO is 0.021e and in NO 0.028e. It is also worth mentioning that xenon (Xe), which is a gas with anesthetic properties, is highly soluble in lipid bilayers and most likely acquires its analgesic effects by targeting membrane proteins [41,76].…”