Position and orientational preferences of drug-like compounds in lipid membranes: a computational and NMR approach

Abstract

Permeation of drugs across lipid bilayers is a key factor in dictating how effective they will be. In vivo, the issue is compounded by the presence of drug-exporter proteins such as P-glycoprotein. However, despite intense effort, exactly what controls permeation and susceptibility to export is still poorly understood. In this work we examine two well-studied drugs for which interaction with P-glycoprotein has been studied before: amitriptyline, a known substrate and clozapine, which is not a substrate. Extensive MD simulations, including potential of mean force (PMF) profiles of the compounds in all possible protonation states, reveal that the preferred location of the compounds in different bilayers in different protonation states is remarkably similar. For both molecules in charged states, there is a substantial barrier to crossing the bilayer. Clozapine however, shows an energetic barrier to movement across the bilayer even in a protonation state that results in an uncharged molecule. For amitriptyline there is only a very small barrier of approximately 1.3 kcal mol(-1). Further analysis revealed that the conformational and orientational behavior of the two compounds was also similar, with the sidechain interacting with the lipid headgroups. This effect was much stronger if the sidechain was charged (protonated). These interactions with lipid bilayers were confirmed by NMR ROESY experiments. The results are discussed in terms of their potential interactions with export proteins like P-glycoprotein.

<p>Novel lipophilic SN38 prodrug forming stable liposomes for colorectal carcinoma therapy</p>

“…Meanwhile, the areas per molecule of lipid bilayer decreased with increasing concentration of moeixitecan (Figure 3E). Lipid membrane thickness and the area per molecule are structural parameters that are needed to accurately determine other bilayer structural parameters and are directly related to lipid–lipid, and lipid–protein interactions in biomembranes 37. Our MD simulations results confirmed the experimental results and provided an accurate picture of moeixitecan’s location and effect for lipid bilayers: moeixitecan molecules fold themselves located inside the hydrocarbon chain of the lipid bilayer inducing an increased acyl chain order of the lipid bilayers and lactone ring stability.…”

Delivery of Alpha-Mangostin Using Cyclodextrins through a Biological Membrane: Molecular Dynamics Simulation

“…Currently, there are several studies on the translocation and interaction of a small molecule in the free form across a lipid bilayer [41,49,50], but the release mechanism of these molecules from the βCDs cavity is not fully understood. To investigate the release behavior of MGS/βCDs complexes into the inner leaflet of the lipid bilayer, the free energy profile for delivering the MGS molecule from the CDs pocket through the lipid bilayer was computed and averaged from three independent simulations.…”

“…Currently, there are a number of methods and models that are available to predict the drug permeability across a biological membrane, such as the quantitative structure-permeability relationship models [37], solubility-diffusion theory [38], parallel artificial membrane permeation assay, and heterogeneous dielectric generalized born based models [39]. Alternatively, molecular dynamics simulation plays an important role in determining the dynamics behavior and release process of the drug-CDs complexes at the atomistic level [40,41].…”

Average orientation of a fluoroaromatic molecule in lipid bilayers from DFT-informed NMR measurements of 1H–19F dipolar couplings

“…The orientational preference of a molecule within cell membranes can not only influence its activity, but may also affect its interaction with efflux transporters that export drugs from the bilayer back into the blood-stream. 2 It is estimated that as many of 30% of new approved drugs contain fluoroaromatic or fluoroalkyl groups. 3 …”

“…For small, drug-like organic molecules in large vesicles, where rotational diffusion within the lipid bilayer is rapid and the rates of vesicle tumbling and drug lateral diffusion within the bilayer are slow, the anisotropic nuclear spin interactions (chemical shielding, dipole–dipole and quadrupolar for I ≥ 1) are averaged in a predictable way. 2 , 4 – 8 NMR line shape analysis provides information about the nature of the dynamic process giving rise to the scaled interactions, such as the average orientation of the lipophile relative to the bilayer normal. These measurements often require isotope labelling with 13 C, 15 N or 2 H to enhance sensitivity, which can be costly and technically demanding.…”