Chapter 9
Simulations of Drug Diffusion in Biomembranes 1
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Terry R. Stouch, Howard E. Alper , and Donna Bassolino Department of Macromolecular Structure, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08654
Bioavailability, largely due to membrane permeation, is an important step in the drug delivery process and therefore drug design. Here we discuss, over 10nsec of molecular dynamics simulation of small molecules in lipid bilayer membranes that were used to elucidate the mechanism of diffusion of drugs within biomembranes. These simulations accurately reproduce many experimentally observed parameters. The simulations also agree with theory that indicates the lipids have internal structure that influences the diffusion process. These simulations show that even within the hydrocarbon chains there are distinct regions between which the rate and mechanism of diffusion varies. These variations are linked to the frequency and size of spontaneously arising voids within the bilayer as well as the rate of torsional isomerization of the hydrocarbon chains.
Bioavailability is an important component of drug efficacy. Many promising drug candidates have been abandoned because of their inability to travel from their site of administration to their site of action. Needless to say, this process is the subject of much research. Often, bioavailability is dependent on passive transport across biological membranes. Correlations are often drawn between a molecule's bioavailability and its partition coefficient between water and organic phases (7). These coefficients are a thermodynamic measure of the relative solubility of a compound between the phases. Membrane
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0097-6156/95A)589-0127$12.00/0 © 1995 American Chemical Society In Computer-Aided Molecular Design; Reynolds, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1995.
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COMPUTER-AIDED M O L E C U L A R DESIGN
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permeation, however, is a measure of the flux of a compound from one side of a membrane to another and includes, in addition to relative solubility, the rate of movement within the membrane. Correlations have also been drawn between permeability itself and partition coefficients. Although these correlations are good for many molecules, they do not universally hold. Small molecules (MW ~
