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Prediction of the permeability of neutral drugs inferred from their solvation properties.

ABSTRACT: Determination of drug absorption is an important component of the drug discovery and development process in that it plays a key role in the decision to promote drug candidates to clinical trials. We have developed a method that, on the basis of an analysis of the dynamic distribution of water molecules around a compound obtained by molecular dynamics simulations, can compute a parameter-free value that correlates very well with the compound permeability measured using the human colon adenocarcinoma (Caco-2) cell line assay.The method has been tested on twenty-three neutral drugs for which a consistent set of experimental data is available. We show here that our method reproduces the experimental data better than other existing tools. Furthermore it provides a detailed view of the relationship between the hydration and the permeability properties of molecules.anna.tramontano@uniroma1.itSupplementary data are available at Bioinformatics online.

SUBMITTER: Milanetti E

PROVIDER: S-EPMC4824127 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Prediction of the permeability of neutral drugs inferred from their solvation properties.

Milanetti Edoardo E Raimondo Domenico D Tramontano Anna A

Bioinformatics (Oxford, England) 20151210 8

<h4>Motivation</h4>Determination of drug absorption is an important component of the drug discovery and development process in that it plays a key role in the decision to promote drug candidates to clinical trials. We have developed a method that, on the basis of an analysis of the dynamic distribution of water molecules around a compound obtained by molecular dynamics simulations, can compute a parameter-free value that correlates very well with the compound permeability measured using the huma ...[more]

PMID: 26656568

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Project description:Alcohol solvents are significantly more polar than expected based on the measured H-bonding properties of monomeric alcohols in dilute solution. Self-association of alcohols leads to formation of cyclic aggregates and linear polymeric chains that have a different polarity from the alcohol monomer. Cyclic aggregates are less polar than the monomer, and the chain ends of linear polymers are more polar. The solvation properties of alcohols therefore depend on the interplay of these self-association equilibria and the equilibria involving interactions with solutes. Twenty-one different molecular recognition probes of varying polarity were used to probe the solvation properties of alkane-alcohol mixtures across a wide range of different solvent compositions. The results allow dissection of the complex equilibria present in these systems. Formation of a H-bond between two alcohol molecules leads to polarisation of the hydroxyl groups, resulting in an increase in binding affinity for subsequent interactions with the unbound donor and acceptor sites. The H-bond donor parameter (α) for these sites increases from 2.7 to 3.5, and the H-bond acceptor parameter (β) increases from 5.3 to 6.9. Polarisation is a short range effect limited to the first H-bond in a chain, and formation of subsequent H-bonds in longer chains does not further increase the polarity of chain ends. H-bond donor sites involved in a H-bond are unavailable for further interactions, because the formation of a bifurcated three-centre H-bond is three orders of magnitude less favourable than formation of a conventional two-centre H-bond. These findings are reproduced by quantum chemical calculations of the molecular electrostatic potential surfaces of alcohol aggregates. Thus, the overall solvation properties of alcohols depend on the speciation of different aggregates, the polarities of these species and the polarities of the solutes. At low alcohol concentrations, polar solutes are solvated by alcohol monomers, and at higher alcohol concentrations, solutes are solvated by the more polar chain ends of linear polymers. The less polar cyclic aggregates are less important for interactions with solutes. Similar behavior was found for ten different alcohol solvents. Tertiary alcohols are marginally less polar solvents than primary alcohols, due to steric interactions that destabilises the formation of polymeric aggregates leading to lower concentrations of polar chain ends. One alcohol with an electron-withdrawing substituent was studied, and this solvent showed slightly different behavior, because the H-bond donor and acceptor properties are different.

Project description:The purpose of this study was to determine corneal permeability and uptake in rabbit, porcine, and bovine corneas for twenty-five drugs using an N-in-1 (cassette) approach and relate these parameters to drug physicochemical properties and tissue thickness through quantitative structure permeability relationships (QSPRs). A twenty-five-drug cassette containing β-blockers, NSAIDs, and corticosteroids in solution at a micro-dose was exposed to the epithelial side of rabbit, porcine, or bovine corneas mounted in a diffusion chamber, and the corneal drug permeability and tissue uptake were monitored using an LC-MS/MS method. Data obtained were used to construct and evaluate over 46,000 quantitative structure-permeability (QSPR) models using multiple linear regression, and the best-fit models were cross-validated by Y-randomization. Drug permeability was generally higher in rabbit cornea and comparable between bovine and porcine corneas. Permeability differences between species could be explained in part by differences in corneal thickness. Corneal uptake between species correlated with a slope close to 1, indicating generally similar drug uptake per unit weight of tissue. A high correlation was observed between bovine, porcine, and rabbit corneas for permeability and between bovine and porcine corneas for uptake (R2 ≥ 0.94). MLR models indicated that drug characteristics such as lipophilicity (LogD), heteroatom ratio (HR), nitrogen ratio (NR), hydrogen bond acceptors (HBA), rotatable bonds (RB), index of refraction (IR), and tissue thickness (TT) are of great influence on drug permeability and uptake. When data for all species along with thickness as a parameter was used in MLR, the best fit equation for permeability was Log (% transport/cm2·s) = 0.441 LogD - 8.29 IR + 8.357 NR - 0.279 HBA - 3.833 TT + 10.432 (R2 = 0.826), and the best-fit equation for uptake was Log (%/g) = 0.387 LogD + 4.442 HR + 0.105 RB - 0.303 HBA - 2.235 TT + 1.422 (R2 = 0.750). Thus, it is feasible to explain corneal drug delivery in three species using a single equation.

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Prediction of the permeability of neutral drugs inferred from their solvation properties.

Publications

Prediction of the permeability of neutral drugs inferred from their solvation properties.

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