version date: 1 December 2006 HYDROPHOBICITY measured as waterloctanol partition coefficient Pa octan [octanol log Pa = log water logP>0→ lipid phase ogP<0→ water phase Panel 1 Fi As an experimental alternative, high-performance liquid chromatography(HPLC)is used for more hydrophobic compounds ranging from 0 to 6 log P values. Log P can be experimentally measured, or predicted from structural data. Experimental measurements are often time-consuming and difficult to make, thus, the need to properly and rapidly estimate hydrophobic parameters more and more pressing. This need was also triggered by the advent of molecular modeling and the screening of large molecular libraries in the perspective of virtual screening and drug design Simultaneously, with new computational applications and molecular modeling progress and achievements, several methods, capable of predicting log P values for thousand of compounds, have been developed, and can now be classified into five major classes [14]: substituent methods fragments methods, methods based on atomic contribution and/or surface areas. methods based on molecular properties, and, finally, methods based on solvatochromic parameters The first"by substituent"approach was proposed by Fujita and coworkers in 1964 [15]. Their technique is based on the following equation log Px-log Pe where Px represents the partition coefficient of a derivative between 1-octanol and water and Ph that of the parent compound. Being that T typically is derived from equilibrium processes, it is possible to directly consider it as a free energy constant. As a consequence, log P represents additive-constitutive, free energy-related property, numerically equivalent to the sum of the parent log P compound, plus a T term, representing the log P difference between a determinate substituent and the hydrogen atom which邮 eplasednble/mt是88￥ tthe log P determination for3 Panel 1 Fig. 1 As an experimental alternative, high-performance liquid chromatography (HPLC) is used for more hydrophobic compounds ranging from 0 to 6 log P values. Log P can be experimentally measured, or predicted from structural data. Experimental measurements are often time-consuming and difficult to make, thus, the need to properly and rapidly estimate hydrophobic parameters is more and more pressing. This need was also triggered by the advent of molecular modeling and the screening of large molecular libraries in the perspective of virtual screening and drug design. Simultaneously, with new computational applications and molecular modeling progress and achievements, several methods, capable of predicting log P values for thousand of compounds, have been developed, and can now be classified into five major classes [14]: substituent methods, fragments methods, methods based on atomic contribution and/or surface areas, methods based on molecular properties, and, finally, methods based on solvatochromic parameters. The first “by substituent” approach was proposed by Fujita and coworkers in 1964 [15]. Their technique is based on the following equation: π = log PX – log PH where PX represents the partition coefficient of a derivative between 1-octanol and water and PH that of the parent compound. Being that π typically is derived from equilibrium processes, it is possible to directly consider it as a free energy constant. As a consequence, log P represents an additive-constitutive, free energy-related property, numerically equivalent to the sum of the parent log P compound, plus a π term, representing the log P difference between a determinate substituent and the hydrogen atom which has been replaced [16]. As an example, the log P determination for water octanol water octanol [A] [A] log PA = log log P > 0 ⇒ lipid phase log P < 0 ⇒ water phase HYDROPHOBICITY measured as water/octanol partition coefficient PA <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006