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Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds.

ABSTRACT: Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous solubility-diffusion model, which requires calculation of the potential of mean force and position-dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the permeability of a model DMPC bilayer to urea, benzoic acid, and codeine. We compare umbrella sampling, replica exchange umbrella sampling, adaptive biasing force, and multiple-walker adaptive biasing force for the calculation of the transmembrane PMF. No definitive advantage for any of these methods in their ability to predict the membrane permeability coefficient Pm was found, provided that a sufficiently long equilibration is performed. For diffusivities, a Bayesian inference method was compared to a generalized Langevin method, both being sensitive to chosen parameters and the slow relaxation of membrane defects. Agreement within 1.5 log units of the computed Pm with experiment is found for all permeants and methods. Remaining discrepancies can likely be attributed to limitations of the force field as well as slowly relaxing collective movements within the lipid environment. Numerical calculations based on model profiles show that Pm can be reliably estimated from only a few data points, leading to recommendations for calculating Pm from simulations.

SUBMITTER: Lee CT

PROVIDER: S-EPMC5280572 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds.

Lee Christopher T CT Comer Jeffrey J Herndon Conner C Leung Nelson N Pavlova Anna A Swift Robert V RV Tung Chris C Rowley Christopher N CN Amaro Rommie E RE Chipot Christophe C Wang Yi Y Gumbart James C JC

Journal of chemical information and modeling 20160414 4

Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous solubility-diffusion model, which requires calculation of the potential of mean force and position-dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the ...[more]

PMID: 27043429

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Project description:Among healthy vegetables, those of the genus Allium stand out. Antioxidant and anti-inflammatory properties have been associated with these vegetables, attributed mainly to organosulfur compounds (OSCs). In turn, they are linked to a protective effect counteracting cardiovascular disease development. Now, to really ensure the bioactive efficacy of the said compounds once consumed, it is necessary to previously evaluate the ADME (absorption, distribution, metabolism, and excretion) profile. Alternatively, in vitro and in silico methods attempt to avoid or reduce experimental animals' use and provide preliminary information on drugs' ability to overcome the various biological barriers inherent in the ADME process. In this sense, in silico methods serve to provide primary information on drugs' bioavailability mechanisms. High-performance liquid chromatography (HPLC) using a stationary phase composed of phospholipids, the so-called immobilized artificial membrane (IAM), has been widely recognized as a valuable alternative method to extract and quantify information about the structure and physicochemical properties of organic compounds which are extensively used in studies of quantitative structure-activity relationships (QSARs). In the present study, the chromatographic capacity factors (log k' (IAM)) for 28 OSCs were determined by IAM-HPLC. In order to evaluate the ability of the IAM phase in assessing lipophilicity of the compounds under study, several quantitative structure-retention relationships (QSRRs) were derived from exploring fundamental intermolecular interactions that govern the retention of compounds under study on IAM phases. As expected, the hydrophobic factors are of prime importance for the IAM retention of these compounds. However, the molecular flexibility and specific polar interactions expressed by several electronic descriptors (relative negative charge, RNCG, and Mulliken electronegativity) are also involved. We also evaluated the IAM phase ability to assess several ADME parameters for the OSCs under study obtained using the SwissADME web tool integrated into the SwissDrugDesign workspace and the PreADMET web tool. The human gastrointestinal absorption (HIA), blood-brain barrier (BBB) permeation, and skin permeability were investigated through QSAR modeling, using several chemometric approaches. The ADME properties under study are strongly dependent on hydrophobic factors as expressed by log k'(IAM), which provide evidence for the great potential of the IAM phases in the development of QSAR models.

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Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds.

Publications

Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds.

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