Specifics of Non‐Specific Drug‐Membrane Interactions Affecting Drug Action and Disposition: Membrane Permeability, Location and Orientation

Objective Membrane partitioning of drugs to a discrete energy favorable location, orientation, and conformation is critical for drug binding to membrane receptors such as GPCRs and ion‐channels, membrane‐bound enzymes such as cytochrome P450s, and efflux transporters such as P‐glycoprotein, affecting drug action and disposition. The location of nonspecific binding sites for a drug molecule within the membrane lipid bilayer have been shown to affect how that drug approaches its specific binding site on a membrane associated receptor; and thus knowledge of the orientation and conformation it adopts in the bilayer may be crucial in understanding its action at the binding site. The traditional methods for assessing the ‘lipophilicity’ of drugs such as measurement of partition coefficients in 1‐octanol/buffer system are inadequate for many drugs. The anisotropic bilayer structure, in contrast to an isotropic surrogate phases has very different physical and chemical characteristics as a function of distance along the bilayer normal axis, including higher surface‐to‐volume ratio. The process of drug partitioning within the membrane appears to exploit these differences in achieving an energetically favorable location, orientation, and conformation. Our previous study (Mol. Pharmaceutics, 2014, 11, 3577–3595) reported a good agreement between experimentally determined bilayer locations of 27 chemicals and that of predicted using a novel surrogate system containing hexadecane/diacetyl phosphatidylcholine (C16/DAcPC) that mimics the phospholipid bilayer more realistically than 1‐octanol/buffer system. This present study investigates the free energy of lipid bilayer partitioning, membrane location and orientation of these molecules using atomistic molecular dynamic simulations. Methods The membrane partitioning characteristics of the studied chemicals (the potential mean force, PMF along the bilayer normal, time average locations and orientations) were investigated in dimyristoyl phosphatidylcholine (DMPC) model membrane system by Umbrella Sampling molecular dynamic simulations, using GPU version of NAMD2.12. The model membrane system and chemicals were parameterized using the CHARMM36 and CGenFF force fields respectively. Results The results from the PMF calculations and atomistic details of interactions from MD trajectory analysis revealed a close agreement with the predicted time‐average location and orientation for majority of the studied chemicals by the surrogate (C16/DAcPC) system. However, the assumption that molecules partition in extended conformation and thus consideration of only extended conformations in head/core interface poses resulted in erroneous omission of critical poses identified during MD for some compounds. Conclusions The obtained results from this study supports that the C16/DAcPC surrogate system accounts for majority of the drug‐membrane interactions and more closely mimic the phospholipid bilayer than the traditional systems. This study also reveals a critical deficiency in the existing interface pose generation method that warrants improvement, and suggests combining MD simulation as an essential tool for investigating membrane‐drug interactions. Support or Funding Information Washington State University This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .