Defining optimum lipophilicity and molecular weight ranges for drug candidates—Molecular weight dependent lower logD limits based on permeability

Waring, Michael J.

doi:10.1016/j.bmcl.2009.03.109

Cited by 269 publications

(179 citation statements)

References 26 publications

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“…We reason that an additional parameter is affecting our observed trends, namely solubility. With regard to peptides, increasing the lipophilicity would be expected to reduce solubility, as suggested recently [41] and as seen with small molecules [42], and thereby affect permeability. This is probably because increased lipophilicity might lead to peptide aggregation or sequester the peptides in the lipid membrane due to less favorable interactions in the aqueous phase.…”

mentioning

confidence: 92%

“…We anticipate that our 'island' may shift for peptides with larger molecular weights than those used in this study. As reported for small molecules, an increased lipophilicity is required to obtain sufficient oral uptake as molecular weight increases [42]. A disadvantage of increasing lipophilicity of small molecules is that increased lipophilicity is known to be correlated to higher levels of target promiscuity [49], as well as increased risks of in vivo animal toxicity [50].…”

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confidence: 99%

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Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Wang

Northfield

Swedberg

et al. 2015

European Journal of Medicinal Chemistry

108

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An increasing number of macrocyclic peptides that cross biological membranes are being reported, suggesting that it might be possible to develop peptides into orally bioavailable therapeutics; however, current understanding of what makes macrocyclic peptides cell permeable is still limited. Here, we synthesized 62 cyclic hexapeptides and characterized their permeability using in vitro assays commonly used to predict in vivo absorption rates, i.e. the Caco-2 and PAMPA assays. We correlated permeability with experimentally measured parameters of peptide conformation obtained using rapid methods based on chromatography and nuclear magnetic resonance spectroscopy. Based on these correlations, we propose a model describing the interplay between peptide permeability, lipophilicity and hydrogen bonding potential. Specifically, peptides with very high permeability have high lipophilicity and few solvent hydrogen bond interactions, whereas peptides with very low permeability have low lipophilicity or many solvent interactions. Our model is supported by molecular dynamics simulations of the cyclic peptides calculated in explicit solvent, providing a structural basis for the observed correlations. This prospective exploration into biomarkers of peptide permeability has the potential to unlock wider opportunities for development of peptides into drugs.3

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confidence: 92%

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confidence: 99%

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Wang

Northfield

Swedberg

et al. 2015

European Journal of Medicinal Chemistry

108

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“…1,2 In studies of extensive datasets of small molecules, the fundamental properties of molecular size, lipophilicity, shape and polarity have been correlated, to varying degrees, with solubility 3 , membrane permeability 4 , metabolic stability, 5,6 receptor promiscuity, 7 in vivo toxicity, 8,9 and attrition 10,11 in drug development pipelines.…”

Section: Introductionmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

945

928

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Summary Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC 50 or KicLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets. Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physical properties, is a practical means of estimating target 'druggability.' This is exemplified with 480 targetassay pairs from the primary literature. Across these targets correlations between biological activity in vitro and physical properties are generally weak, showing that increasing activity by increasing physical properties is not always necessary. Charles H. ReynoldsCharles Reynolds is currently President of Gfree Bio, a modeling and structure-based design company in AbstractThe judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates.

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“…It is related to the distribution of compounds in the environment and biota, to bioavailability and bioconcentration in the food chain, as well as to the transport in the soil-sediment-water compartments [1]. It is a crucial factor influencing passive transport trough biological membranes such as the blood-brain or the gastrointestinal barriers [2,3]. Lipophilicity has a high impact on protein binding, drug-receptor interactions, which consequentially alters the desired physiological response, as well as drug-related toxicity and adverse effects [4,5].…”

Section: Introductionmentioning

confidence: 99%

“…2. (2) where R F is the retardation factor, i.e., the ratio of the distance of a solute target zone and the solvent front.…”

Section: Introductionmentioning

confidence: 99%

Multivariate assessment of lipophilicity scales—computational and reversed phase thin-layer chromatographic indices

Andrić

Bajusz

Rácz

et al. 2016

Journal of Pharmaceutical and Biomedical Analysis

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Needs for fast, yet reliable means of assessing the lipophilicities of diverse compounds resulted in the development of various in silico and chromatographic approaches that are faster, cheaper, and greener compared to the traditional shake-flask method. However, at present no accepted "standard" approach exists for their comparison and selection of the most appropriate one(s). This is of utmost importance when it comes to the development of new lipophilicity indices, or the assessment of the lipophilicity of newly synthesized compounds. In this study, 50 well-known, diverse compounds of significant pharmaceutical and environmental importance have been selected and examined. Octanol-water partition coefficients have been measured with the shake-flask method for most of them. Their retentions have been studied in typical reversed thin-layer chromatographic systems, involving the most frequently employed stationary phases (octadecyl-and cyano-modified silica), and acetonitrile and methanol as mobile phase constituents. Twelve computationally estimated logP-s and twenty chromatographic indices together with the shake-flask octanol-water partition coefficient have been investigated with classical chemometric approaches -such as principal component analysis (PCA), hierarchical cluster analysis (HCA), Pearson's and Spearman's correlation matrices, as well as novel non-parametric methods: sum of ranking differences (SRD) and generalized pairwise correlation method (GPCM). Novel SRD and GPCM methods have been introduced based on the Comparisons with One VAriable (lipophilicity metric) at a Time (COVAT). For the visualization of COVAT results, a heatmap format was introduced. Analysis of variance (ANOVA) was applied to reveal the dominant factors between computational logPs and various chromatographic measures. In consensusbased comparisons, the shake-flask method performed the best, closely followed by computational estimates, while the chromatographic estimates often overlap with in silico assessments, mostly with methods involving octadecylmodified silica stationary phases. The ones that employ cyano-modified silica perform generally worse. The introduction of alternative coloring schemes for the covariance matrices and SRD/GPCM heatmaps enables the discovery of intrinsic relationships among lipophilicity scales and the selection of best/worst measures. Closest to the recommended logK OW values are ClogP and the first principal component scores obtained on octadecyl-silica stationary phase in combination with methanol-water mobile phase, while the usage of slopes derived from Soczewinski-Matyisik equation should be avoided.

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Defining optimum lipophilicity and molecular weight ranges for drug candidates—Molecular weight dependent lower logD limits based on permeability

Cited by 269 publications

References 26 publications

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

The role of ligand efficiency metrics in drug discovery

Multivariate assessment of lipophilicity scales—computational and reversed phase thin-layer chromatographic indices

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