version date: 1 December 2006 to stick to the vessel walls; this is compounded by the accuracy of the assay procedure when a purported method to estimate log P claims accuracy to within 1 log unit, it must surely scare and, as any estimation method that claims to be better than experimental error, seems somehow surreal. Using the classic shake-flask method, log P measurements may be very time- consuming. Beginning with the"easy" solutes in the mid-1960s, a technician in Hansch's group usually measured a half-dozen per week, each over at least a five-fold concentration range and with at least three measurements deviating no more than 0.05 log units but the solutes of current inter- est are generally much more difficult to measure, especially those of very high or very low log P where the solvent ratios are 1000 to l or greater For extremely lipophilic solutes, it has been shown that measured log P values can asymp. totically approach a high log p value due to the global dissolving effect of octanol in the aqueous Thus, the accuracy of measurements of these excessively lipophilic solutes is not as much a problem as is the fact that the octanol/water model no longer reflects real-life situations Theoretical approaches for log P calculation are required to estimate its value for hypotheti cal structures, such as those that may be designed based on the QSars developed Several methods that allow the computation of partition coefficients have been proposed Each of these methods varies considerably in its rationale The partition coefficient of a solute in two solvents may be approximated as the ratio of its solubilities in the two solvents. The logarithm of partition coefficient, on the other hand, is directly lated to the change in free energy during the transfer of the solute from one solvent to the other One way of understanding the octanol/water partition coefficient is to correlate it with more fun- damental physicochemical properties, like molar volume, formal charge density, and polarizability With some modification, the atomic values of these fundamental properties can then be used to get the atomic contributions to partition coefficient. Although this approach is scientifically attractive there are several problems with it, particularly the conformational dependency of these fundamental properties for conformationally flexible molecules While a variety of different approaches have been proposed in the past for the computation of this property, most of them are based on two-dimensional molecular topology(vide infra). This feature renders them inadequate to describe the dependence of hydrophobicity on the three- dimensional arrangement of atoms. However, since flexible compounds can adopt different con- formations in solvents of different polarity, this dependence of the hydrophobic character on struc ture is a significant property. For instance, dependency of the conformation on the environment can be used in conjunction with other properties to identify the bioactive form for d i.e. the form in which the drug binds to the receptor The hydrophobicity of a molecular system depends on the nature of the groups exposed to interaction with the environment, and, therefore, it is dependent on the conformation of the system, whereas log P is not. Then, when three-dimensional structural properties of the ligands are included either in QSAR, COMF A analysis, or in mechanistic-based deduction of molecular determinants of receptor recognition, the use of log P is insufficient. A simple method to extend its usefulness would be to modify log P to relate to structure. However, it is possible to develop this relationship only for rigid analogs since in this case the interactions between the solute and the solvent are uniquely defined. Then, the relation thus established for rigid analogs can be used to characterize the hydrophobicity of particular conformations of flexible analogs. Such a conformationally de pendent hydrophobicity parameter would be a useful addition to other properties routinely used to characterize the bioactive structure of a ligand when no structural information about the receptor known. Without this information, the form of the ligand that is recognized by the receptor, i.e., its bioactive form is then deduced for each ligand based on the similarities in steric and electronic properties for analogs with high binding affinities and on the dissimilarities with all other analogs The lack of conformationally dependent hydrophobicity criteria prevents the use of this property mong those analyzed, in this crucial step toward the development of a pharmacophore <www.iupac.org/publications/cd/medicinalchemistryl>2 molecules to stick to the vessel walls; this is compounded by the accuracy of the assay procedure itself). So, when a purported method to estimate log P claims accuracy to within 1 log unit, it must surely scare and, as any estimation method that claims to be better than experimental error, seems somehow surreal. Using the classic shake-flask method, log P measurements may be very time￾consuming. Beginning with the “easy” solutes in the mid-1960s, a technician in Hansch’s group usually measured a half-dozen per week, each over at least a five-fold concentration range and with at least three measurements deviating no more than 0.05 log units. But the solutes of current inter￾est are generally much more difficult to measure, especially those of very high or very low log P where the solvent ratios are 1000 to 1 or greater. For extremely lipophilic solutes, it has been shown that measured log P values can asymp￾totically approach a high log P value due to the global dissolving effect of octanol in the aqueous phase. Thus, the accuracy of measurements of these excessively lipophilic solutes is not as much a problem as is the fact that the octanol/water model no longer reflects real-life situations. Theoretical approaches for log P calculation are required to estimate its value for hypotheti￾cal structures, such as those that may be designed based on the QSARs developed. Several methods that allow the computation of partition coefficients have been proposed. Each of these methods varies considerably in its rationale. The partition coefficient of a solute in two solvents may be approximated as the ratio of its solubilities in the two solvents. The logarithm of partition coefficient, on the other hand, is directly related to the change in free energy during the transfer of the solute from one solvent to the other. One way of understanding the octanol/water partition coefficient is to correlate it with more fun￾damental physicochemical properties, like molar volume, formal charge density, and polarizability. With some modification, the atomic values of these fundamental properties can then be used to get the atomic contributions to partition coefficient. Although this approach is scientifically attractive, there are several problems with it, particularly the conformational dependency of these fundamental properties for conformationally flexible molecules. While a variety of different approaches have been proposed in the past for the computation of this property, most of them are based on two-dimensional molecular topology (vide infra). This feature renders them inadequate to describe the dependence of hydrophobicity on the three￾dimensional arrangement of atoms. However, since flexible compounds can adopt different con￾formations in solvents of different polarity, this dependence of the hydrophobic character on struc￾ture is a significant property. For instance, dependency of the conformation on the environment can be used in conjunction with other properties to identify the bioactive form for a ligand, i.e., the form in which the drug binds to the receptor. The hydrophobicity of a molecular system depends on the nature of the groups exposed to interaction with the environment, and, therefore, it is dependent on the conformation of the system, whereas log P is not. Then, when three-dimensional structural properties of the ligands are included either in QSAR, COMFA analysis, or in mechanistic-based deduction of molecular determinants of receptor recognition, the use of log P is insufficient. A simple method to extend its usefulness would be to modify log P to relate to structure. However, it is possible to develop this relationship only for rigid analogs since in this case the interactions between the solute and the solvent are uniquely defined. Then, the relation thus established for rigid analogs can be used to characterize the hydrophobicity of particular conformations of flexible analogs. Such a conformationally de￾pendent hydrophobicity parameter would be a useful addition to other properties routinely used to characterize the bioactive structure of a ligand when no structural information about the receptor is known. Without this information, the form of the ligand that is recognized by the receptor, i.e., its bioactive form is then deduced for each ligand based on the similarities in steric and electronic properties for analogs with high binding affinities and on the dissimilarities with all other analogs. The lack of conformationally dependent hydrophobicity criteria prevents the use of this property, among those analyzed, in this crucial step toward the development of a pharmacophore. <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006