version date: 1 December 2006 The characterization of a bioactive form is already one of the most challenging tasks in the development of pharmacophores for the computer-assisted design of novel drugs. Except for totally rigid analogs, the conformation in which the drug interacts with the receptor does not need to be its minimum energy structure. In most cases, candidate bioactive forms result from the analysis of steric and electronic similarities and dissimilarities among analogs with pharmacological profiles Hence, inclusion of information relative to influence of conformational dependence on key phys- icochemical properties of these compounds should facilitate the characterization of the bioactive Hopfinger and Bartell developed a solvent-dependent conformational analysis that allowed le computation of partition coefficients. The method was based on the precise evaluation of the first solvation shell far each solvent, making it computationally expensive A variation of the atomic contributions method was developed by Klopman and coworkers a quantum mechanical parameterization based on the computation of charge densities The rationale behind this latter approach is that the partition coefficient depends on the relative solubility of a substrate in a polar and nonpolar solvent. Since solubility in a polar envi- ronment can in turn be related to the electrostatic forces that involve charge densities, they post lated that the partition coefficient of a molecule should also be dependent on the charge densities More recently, Bodor et al. expanded the method originally developed by Klopman and co workers to include several other quantities such as the total molecular surface and its globularity, properties that are confomationally dependent, as well as the molecular weight, dipole moment,a olynomial of the sum of the atomic charges per atom, and an empirical parameter that assumed different values depending on the chemical family. Richards and coworkers have also developed a program called hYdRo that allows the computation of a conformation-dependent hydrophobic in- dex. The method consists of a series of fragment transfer free energies which are a function of the solvent-accessible surface area An atom-based method for the computation of a conformationally dependent hydrophobic index(p) is that by villa ar(see The alternate approach is to express the octanol/water partition coefficient in terms of the chemical structure of the ligand. Rekker et al. first gave some fragmental values for calculating the partition coefficient from the chemical structure of the molecules. Hansch and Leo followed the same direction and gave a thorough list of fragmental values and also a large number of correction factors to account for various intramolecular interactions. The implementation of these latter values in the CloGP program is the most reliable and widely used technique for the theoretical determi- nation of the partition coefficient. The calculation of the partition coefficient is performed by add- ing the contributions of molecular fragments. The major task in this method is the adequate definition of the fragments needed to generate a consistent parameterization. It is due to these cor- rection factors that regional contributions toward the partition coefficient are difficult to evaluate Alternative methods to determine this property are based on the addition of atomic contri butions, such as the methods developed by broto et al. and ghose et al. In this approach, tables of contributions for atoms in different topologic environments are used. The major advantage of this technique is that it lends itself to simple automation The solvatochromic approach pioneered by Kamlet, Taft, or that by Taylor, Leahy, Abra- ham points out that other partitioning pairs can add valuable information that log P octanol lacks a good program should provide some"distillation" of the hard-won wisdom contained in some hundreds of papers most researchers will not have read. The future challenge in improving log P(oct)calculation programs is to convey to the user as much understanding as possible of what determines the final parameter value, for instance, (i) predicting when a lipophilic environment en- intramolecular hydrogen bond to form when the solute is through a membrane or in a lipophilic pocket at the active site; (ii) the same sort of prediction when tautomerism is pos sible, e.g., encouraging the more lipophilic enol over the keto <www.iupac.org/publications/cd/medicinal_chemistry/>3 The characterization of a bioactive form is already one of the most challenging tasks in the development of pharmacophores for the computer-assisted design of novel drugs. Except for totally rigid analogs, the conformation in which the drug interacts with the receptor does not need to be its minimum energy structure. In most cases, candidate bioactive forms result from the analysis of steric and electronic similarities and dissimilarities among analogs with pharmacological profiles. Hence, inclusion of information relative to influence of conformational dependence on key phys￾icochemical properties of these compounds should facilitate the characterization of the bioactive form. Hopfinger and Bartell developed a solvent-dependent conformational analysis that allowed the computation of partition coefficients. The method was based on the precise evaluation of the first solvation shell far each solvent, making it computationally expensive. A variation of the atomic contributions method was developed by Klopman and coworkers: a quantum mechanical parameterization based on the computation of charge densities. The rationale behind this latter approach is that the partition coefficient depends on the relative solubility of a substrate in a polar and nonpolar solvent. Since solubility in a polar envi￾ronment can in turn be related to the electrostatic forces that involve charge densities, they postu￾lated that the partition coefficient of a molecule should also be dependent on the charge densities. More recently, Bodor et al. expanded the method originally developed by Klopman and co￾workers to include several other quantities such as the total molecular surface and its globularity, properties that are confomationally dependent, as well as the molecular weight, dipole moment, a polynomial of the sum of the atomic charges per atom, and an empirical parameter that assumed different values depending on the chemical family. Richards and coworkers have also developed a program called HYDRO that allows the computation of a conformation-dependent hydrophobic in￾dex. The method consists of a series of fragment transfer free energies, which are a function of the solvent-accessible surface area. An atom-based method for the computation of a conformationally dependent hydrophobic index (p) is that by Villar (see below). The alternate approach is to express the octanol/water partition coefficient in terms of the chemical structure of the ligand. Rekker et al. first gave some fragmental values for calculating the partition coefficient from the chemical structure of the molecules. Hansch and Leo followed the same direction and gave a thorough list of fragmental values and also a large number of correction factors to account for various intramolecular interactions. The implementation of these latter values in the CLOGP program is the most reliable and widely used technique for the theoretical determi￾nation of the partition coefficient. The calculation of the partition coefficient is performed by add￾ing the contributions of molecular fragments. The major task in this method is the adequate definition of the fragments needed to generate a consistent parameterization. It is due to these cor￾rection factors that regional contributions toward the partition coefficient are difficult to evaluate. Alternative methods to determine this property are based on the addition of atomic contri￾butions, such as the methods developed by Broto et al. and Ghose et al. In this approach, tables of contributions for atoms in different topologic environments are used. The major advantage of this technique is that it lends itself to simple automation. The solvatochromic approach pioneered by Kamlet, Taft, or that by Taylor, Leahy, Abra￾ham points out that other partitioning pairs can add valuable information that log P octanol lacks. A good program should provide some “distillation” of the hard-won wisdom contained in some hundreds of papers most researchers will not have read. The future challenge in improving log P(oct) calculation programs is to convey to the user as much understanding as possible of what determines the final parameter value, for instance, (i) predicting when a lipophilic environment en￾courages an intramolecular hydrogen bond to form when the solute is passing through a membrane or in a lipophilic pocket at the active site; (ii) the same sort of prediction when tautomerism is pos￾sible, e.g., encouraging the more lipophilic enol over the keto. <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006