Structure–Kinetic Relationships of Passive Membrane Permeation from Multiscale Modeling

• Published in: Journal of the American Chemical Society Vol. 139; no. 1; pp. 442 - 452
• Main Authors: Dickson, Callum J, Hornak, Viktor, Pearlstein, Robert A, Duca, Jose S
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-01-2017
• Subjects: Animals; Caco-2 Cells; Cell Membrane Permeability; Dogs; Humans; Kinetics; Madin Darby Canine Kidney Cells - chemistry; Models, Chemical; Molecular Dynamics Simulation; Molecular Structure; Quantitative Structure-Activity Relationship; Small Molecule Libraries - chemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b11215

Passive membrane permeation of small molecules is essential to achieve the required absorption, distribution, metabolism, and excretion (ADME) profiles of drug candidates, in particular intestinal absorption and transport across the blood–brain barrier. Computational investigations of this process typically involve either building QSAR models or performing free energy calculations of the permeation event. Although insightful, these methods rarely bridge the gap between computation and experiment in a quantitative manner, and identifying structural insights to apply toward the design of compounds with improved permeability can be difficult. In this work, we combine molecular dynamics simulations capturing the kinetic steps of permeation at the atomistic level with a dynamic mechanistic model describing permeation at the in vitro level, finding a high level of agreement with experimental permeation measurements. Calculation of the kinetic rate constants determining each step in the permeation event allows derivation of structure–kinetic relationships of permeation. We use these relationships to probe the structural determinants of membrane permeation, finding that the desolvation/loss of hydrogen bonding required to leave the membrane partitioned position controls the membrane flip-flop rate, whereas membrane partitioning determines the rate of leaving the membrane.