Lipophilicity in QSAR

Mannhold, R., Dross, K. P., Rekker, R. F. Drug lipophilicity in QSAR practice ... 

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). 

H2O Mannhold. R, Dross KP and Reffer RF, Drug lipophilicity in QSAR... 

Chem., 47,1242-1250 (2004). Ref. 277 Mannhold R, Dross KP and Reffer RF, Drug lipophilicity in QSAR practice I. A comparison of experimental with calculative approaches, Quant. Struct.-Act. Rdat, 9, 21-28 (1990). 

A quite comprehensive section concerns Lipophilicity, one of the most informative physicochemical properties in medicinal chemistry and since long successfully used in QSAR studies. 

This quadratic dependence has been observed in many systems, and the dominance of lipophilicity in controlling activity reflects its importance in transport [74]. Nevertheless, the biological response (BR) of a series of compounds (which is often expressed by the inverse of the drug concentration) may also involve an electronic ( ) and/or a steric (5) contribution. Hence, QSARs have been mostly constructed using the generalized Hansch equation [337] ... 

QSARs based on ionic compounds have thus been dramatically restricted due to the neglect of ion partitioning, which consequently meant that no technique was dedicated to such measurements and that modeling never took account of ionic species. To become fully accepted, potentiometry and electrochemistry at the ITIES need now to prove interesting in QSARs. As numerous lipophilicity data of ionizable compounds become available, one can expect that solvatochromic equations for ions will soon be developed in various solvent systems, which would greatly facilitate QSAR studies. 

The major hurdle to overcome in the development of 3D-QSAR models using steric, electrostatic, or lipophilic fields is related to both conformation selection and subsequent suitable overlay (alignment) of compounds. Therefore, it is of some interest to provide a conformation-ally sensitive lipophilicity descriptor that is alignment-independent. In this chapter we describe the derivation and parametrization of a new descriptor called 3D-LogP and demonstrate both its conformational sensitivity and its effectiveness in QSAR analysis. The 3D-LogP descriptor provides such a representation in the form of a rapidly computable description of the local lipophilicity at points on a user-defined molecular surface. 

The chapter is divided into three sections the first part is concerned with the derivation of 3D-LogP descriptor and the selection of suitable parameters for the computation of the MLP values. This study was performed on a set of rigid molecules in order, at least initially, to avoid the issue of conformation-dependence. In the second part, both the information content and conformational sensitivity of the 3D-LogP description was established using a set of flexible acetylated amino acids and dipeptides. This initial work was carried out using log P as the property to be estimated/predicted. However, it should be made clear that, while the 3D-LogP descriptor can be used for the prediction of log P, this was not the primary intention behind its the development. Rather, as previously indicated, the rationale for this work was the development of a conformationally sensitive but alignment-free lipophilicity descriptor for use in QSAR model development. The use of log P as the property to be estimated/predicted enables one to establish the extent of information loss, if any, in the process used to transform the results of MLP calculations into a descriptor suitable for use in QSAR analyses. 

Although not perfect, Hansch s lipophilicity parameter and log P values are the most widely used parameters in QSAR studies. In addition to their effectiveness in predicting biological activity through target binding (pharmacodynamics), both parameters also affect pharmacokinetics. The pharmacokinetic applications of log P and 7r-values can be seen in Lipinski s rules and a Case Study (Carboxylate Antifungals) later in this chapter. 

Hydrophobicity (or lipophilicity) characterizes the readiness of a molecule to escape or to prefer the water environment. It plays a fundamental role in biochemical processes and influences the fate of a molecule in the environment. Thus, hydrophobic descriptors play an important role in QSAR modeling that is used in drug research and for risk characterization. The most widely used hydrophobic descriptor is the octanol-water partition coefficient (log P) proposed by Hansh [49]. P is a quotient between solubihties in octanol and water. It is defined by following equation ... 

Partitioning between octanol and water is used to determine lipophilicity a factor in QSAR studies. 

Lipophilicity is frequently used in QSAR analysis and expressed as the partition coefficient P (or by its decimal logarithm, log P) between a nonaqueous and aqueous phase. Another parameter, which takes into account the equilibrium of an ionizable compound at a stated pH value, is the distribution coefficient (Z>), which depends on the P of the single species and on the pAT values of the chosen compound. P and D have been evaluated for different N-substituted l,2-benzisothiazol-3-one derivatives using the partition between -octanol and water. Selected data are reported in Table 9 <1996FES493, 2002EJM553>. 

If limited data points are available in QSAR analysis, logP (logD) can be used to account for different degrees of ionization as well as for different lipophilicities. If, on the other hand, a sufficient... 

Well-known substituent descriptors are the substituent constants which are experimentally determined descriptors among them, - electronic substituent constants, steric substituent descriptors, and lipophilicity substituent descriptors such as - Hansch-Fujita hydrophobic constants are the most commonly used in QSAR/QSPR modelling. 

Kubinyi, H. (1995). From Lipophilicity to 3D QSAR - The Fascination of Computer-Aided Drug Design. In QSAR and Molecular Modelling Cocepts, Computatiorml Tools and Biological Applications (Sanz, F, Giraldo, J. and Manaut, F, eds.), Prous Science, Barcelona (Spain), pp. 2-16. 

Langlois, M.H., Audry, E., Croizet, F., Dallet, Ph., Carpy, A. and Dubost, J.P. (1993b). Topological Lipophilicity Potential A New Tool for a Fast Evaluation of Lipophilicity Distribution on a Molecular Graph. In Trends in QSAR and Molecular Modelling 92 (Wennuth, C.G., ed.), ESCOM, Leiden (The Netherlands), pp. 354-355. 

Practical problems in the estimation of the lipophilicity of araliphatic and aliphatic compoimds led to the / hydrophobicity scales of Rekker and Leo/Hansch. However, all such descriptor scales depend on experimental determinations. New molecular descriptors were developed from scratch, starting with the work of Randic, Kier and Hall, i.e. the various molecular connectivity parameters %. Later the electrotopological state parameters and the Todeschini WHIM parameters were added. Whereas topological descriptors are mathematical constructs that have no unique chemical meaning, they are clearly related to some physicochemical properties and are suited to the description of compound similarities in a quantitative manner. Thus, despite several critical comments in the past, they are now relatively widely used in QSAR studies. Only a meaningless and excessive application in quantitative models, as far as the number of tested and included variables is concerned, still deserves criticism. 

To what extent, for example, do hydrophobic parameters depend on electronic changes in the molecule Or how much does the steric parameter, being related to the size of a substituent, contribute to the lipophilicity of the molecule Without understanding of the physicochemical basis of the parameters used in QSAR it is impossible to assess their significance and the validity of the models from which they are derived. In subsequent sections we discuss the physicochemical basis of these parameters. 

Due to its importance in QSAR studies, several approaches were proposed for modeling lipophilicity of chemical compounds. 

Audry, E., Dubost, J.P., Langlois, M.H., Croizet, F Braquet, P., Dallet, Ph. and Colleter, J.C. (1992) Use of molecular lipophilicity potential in QSAR, in QSAR Design of Bioactive Compounds (ed. M. Kuchar), Prous Science, Barcelona, Spain, pp. 249-268. 

In addition to nonlinear lipophilicity relationships for the transport and distribution of drugs, nonlinear relationships on molar refractivity are frequently observed in QSAR studies of enzyme inhibition data (provided that MR values are scaled by a factor of 0.1, as usual) [60,63,64,66-68]. Two such examples are given in Eq. (63) (Escherichia coli DHFR) and Eq. (64) (Lactobacillus casei DHFR) [101]. The differences between both models could be explained after the 3D structure of the enzyme became known. Whereas all substituents of a benzyl ring contribute to biological activities in E. coli DHFR, only the 3- and 4-substituents show up in the QSAR model for L. casei DHFR but not the 5-substituents. This results from a narrower binding pocket in L. casei DHFR a (3-branched leucine hinders the accommodation of 5-substituents, whereas a more flexible methionine in the same position of E. coli DHFR opens a wider binding pocket [101] ... 

Kubinyi H. Lipophilicity and biological activity the use of the bilinear model in QSAR. In Kuchar M ed. QSAR in Design of Bioactive Compounds. Proceedings of the First International Telesymposium on Medicinal Chemistry. Barcelona Prous Science Publishers, 1984 321-346. 

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