Lipophilicity calculation approaches

Mannhold, R., Dross, K.P., and Rekker, R.F., Drug lipophilicity in QSAR practice. I. A comparison of experimental with calculative approaches, Quant. Struct.-Act. Relat., 9, 21-28, 1990. 

Mannhold, R., K. P. Dross, and R. F. Rekker. 1990. Drug lipophilicity in QSAR practice A comparison of experimental with calculated approaches. Quantitative Structure-Activity Relationship 9 21-28. 

Barba to F, Caliendo G, LaRotonda MI, Morrica P, Silipo C and Vittoria A, Relationships between octanol-water partition data, chromatographic indices and their dependence on pH in a set of beta-adrenoceptor blocking agents, Farmaco, 45,647-663 (1990) Mannhold R, Dross KP and Reffer RF, Drug lipophilicity in QSAR practice I. A comparison of experimental with calculative approaches, Quant-Struct.-Act. Relat., 9,21-28 (1990). Cited in Lombardo F, Obach RS, Shalaeva MY and Gao F, Prediction of human volume of distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out statistics, /. Med. Chem., 47, 1242-1250 (2004) (refs 275,277). 

One of the most important characteristics of the emulsifier is its CMC, which is defined as the critical concentration value below which no micelle formation occurs. The critical micelle concentration of an emulsifier is determined by the structure and the number of hydrophilic and hydrophobic groups included in the emulsifier molecule. The hydrophile-lipophile balance (HLB) number is a good criterion for the selection of proper emulsifier. The HLB scale was developed by W. C. Griffin [46,47]. Based on his approach, the HLB number of an emulsifier can be calculated by dividing... 

Rekker, R. F., Mannhold, R. Calculation of Drug Lipophilicity. The Hydrophobic Fragmental Constant Approach, VCH, Weinheim, 1992. 

The presenee of intramoleeular interaetions ean be eheeked by eomparing calculated and experimental log P values. Sueh identifieation ean yet only be obtained for the water-OCT system, sinee eomputed lipophilieity values have only been derived for this solvent pair. Due to its simplicity and its easy adaptation to eomplex structures, Rekker s calculation method is often appreciated, but more sophistieated approaches like that evaluating log P using the molecular lipophilicity potential (MLP) has also been employed. 

In PAMPA measurements each well is usually a one-point-in-time (single-timepoint) sample. By contrast, in the conventional multitimepoint Caco-2 assay, the acceptor solution is frequently replaced with fresh buffer solution so that the solution in contact with the membrane contains no more than a few percent of the total sample concentration at any time. This condition can be called a physically maintained sink. Under pseudo-steady state (when a practically linear solute concentration gradient is established in the membrane phase see Chapter 2), lipophilic molecules will distribute into the cell monolayer in accordance with the effective membrane-buffer partition coefficient, even when the acceptor solution contains nearly zero sample concentration (due to the physical sink). If the physical sink is maintained indefinitely, then eventually, all of the sample will be depleted from both the donor and membrane compartments, as the flux approaches zero (Chapter 2). In conventional Caco-2 data analysis, a very simple equation [Eq. (7.10) or (7.11)] is used to calculate the permeability coefficient. But when combinatorial (i.e., lipophilic) compounds are screened, this equation is often invalid, since a considerable portion of the molecules partitions into the membrane phase during the multitimepoint measurements. 

Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

A modification of the atomic approach was also proposed by Gaillard et al. using molecular lipophilicity potential (MLP) as a 3D source of two lipophilicity parameters calculated from the water-accessible surface, namely a hydrophobic parameter expressed as the sum ofthe positive lipophilicity potential (EM LP+) and a polar parameter expressed as the sum of the negative lipophilicity potential (EMLP—)... 

R. F. Rekker, R. Mannhold, Calculation of drug lipophilicity the hydrophobic fragmentat constant approach, VCH, Weinheim, Germany, 1992. 

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