Journal of Pharmaceutical and Biomedical Analysis 115 (2015) 183–191 Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis j o ur na l ho mepage: www.elsevier.com/locate/jpba Towards better understanding of lipophilicity: Assessment of in silico and chromatographic logP measures for pharmaceutically important compounds by nonparametric rankings Filip Andri ´ c a , Károly Héberger b,∗ a Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia b Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest XI., Magyar Tudósok krt 2, Hungary a r t i c l e i n f o Article history: Received 10 April 2015 Received in revised form 6 July 2015 Accepted 7 July 2015 Available online 17 July 2015 Keywords: Lipophilicity Natural toxins Antifungal drugs Thin-layer chromatography Sum of ranking differences Generalized pairwise-correlation method Multivariate data analysis a b s t r a c t Lipophilicity is one of the most frequently used physicochemical properties that affects compound solubility, determines its passive transport through biological membranes, influences biodistri- bution, metabolism and pharmacokinetics. We compared, ranked and grouped chromatographic lipophilicity indices and computationally estimated logP–s by sensitive and robust non-parametric approaches: sum of ranking differences (SRD) and generalized pairwise correlation method (GPCM). Chromatographic indices of fourteen neurotoxins and twenty one 1,2,4-triazole compounds have been derived from typical reversed-phase thin-layer chromatography and micellar chromatogra- phy. They were compared with in silico estimated logP–s. Under typical reversed-phase conditions, octadecyl-, octyl-, and cyanopropyl-modified silica have clear advantage over ethyl-, aminopropyl- , and diol-modified beds, i.e., the preferable choice of the stationary phase follows this order: octadecyl > octyl > cyanopropyl > ethyl > octadecyl wettable > aminopropyl > diol. Many of these indices outperform the majority of computationally estimated logP–s. Clear distinction can be made based on cross-validation and statistical tests. Oppositely, micellar chromatography may not be successfully used for the lipophilicity assessment, since retention parameters obtained from the typical reversed-phase conditions outperform the parameters obtained by micellar chromatography. Both ranking approaches, SRD and GPCM, although based on different background, provide highly sim- ilar variable ordering and grouping leading to the same, above mentioned conclusions. However, GPCM results in more degeneracy, i.e., in some cases it cannot distinguish the lipophilicity parameters whereas SRD and its cross-validated version can. On the other hand GPCM produces a more characteristic group- ing. Both methods can be successfully used for selection of the most and least appropriate lipophilicity measures. © 2015 Published by Elsevier B.V. 1. Introduction Lipophilicity is one of the major physical–chemical properties used in pharmaceutical and environmental sciences. Its role is of utmost importance in drug discovery [1] and modeling of the fate Abbrevaitions: C18, octadecyl; C18W, octadecyl wettable; C2, ethyl; C8, octyl; CE-PW, conditional exact Fisher test & probability weighted ranking; CMC, critical micellar concentration; CN, cyanopropyl; CRRN, validation of the SRD procedure: comparison of ranks by random numbers; CV, cross-validation; GPCM, generalized pair correlation method; HCA, hierarchical cluster analysis; HPLC, high performance liquid chromatography; IAM, immobilized artificial membrane chromatography; MLC, micellar liquid chromatography; NH2, aminopropyl; OPLC, overpressured layer chromatography; PC, principal component; PCA, principal component analysis; RP, reversed-phase; RP-TLC, reversed-phase thin-layer chromatography; SRD, sum of ranking (absolute) differences; TLC, thin-layer chromatography. ∗ Corresponding author. E-mail address: heberger.karoly@ttk.mta.hu (K. Héberger). of a compound in the environment. It strongly affects compound solubility, and determines passive transport through biological membranes such as gastrointestinal tract or blood to brain barrier [2]. It also influences biodistribution, metabolism and pharmacoki- netics [3]. It significantly impacts the protein binding, modeling of drug-receptor interactions, compound-related toxicity or adverse effects [4]. Among other parameters, such as solubility, stability, acid-base character, etc., lipophilicity is determined at the early stages of drug development, and included in identification of start- ing points, viable chemical leads, and developing candidates [5]. Bioavailability and bioconcentration in the food chain through sorption from water, and soil or sediment, is also affected by lipophilicity [6], which makes it an important factor in risk assess- ment and management of hazardous materials. The octanol–water partition coefficient (logP O/W, or more often written as logP) is generally accepted as the golden standard for lipophilicity measurement (assessment) [6]. The experimental http://dx.doi.org/10.1016/j.jpba.2015.07.006 0731-7085/© 2015 Published by Elsevier B.V.