version date: 1 December 2006 EXERCISE lL. 4 COMPARING LOG P CALCULATIONS BY THE GHOSE-CRIPPEN AND VILLAR METHODS Laura giurato and Salvatore Guccione Department of Pharmaceutical Sciences, University of Catania, viale Andrea Doria 6, Ed 2 Citta Universitaria, /-95125 Catania, Italy Phone:+39 095 738-4020: Fax:+39 095 443604: E-mail: edufarm@unict it(LG); guccione @unict it(SG) Scientific computation is not an end itself. It must be implemented in the context of problems to be solved. Introduction Biological activity is not an invariant property of a geometrical arrangement of a subset of ligand atoms, but it is contingent on parameters of the whole molecule and on interactions external to the molecules themselves, i. e, with the receptor There are three major forces that are important in biochemical ligand binding: hydrophobic, dispersive, and electrostatic interactions. Molar refractivity is related to dispersive forces, and the molecular orbital charge distribution or the electrostatic potential at the van der Waals radius may be used for modeling the electrostatic interaction. However, the hydrophobic interaction, although probably the most important factor for biochemical interaction, is least understood. The term "hy drophobic interaction"refers to the force or the corresponding energy that operates between two or more nonpolar solutes in liquid water. Although the theoretical work on hydrophobic interactions led to a clear understanding of the molecular structure of aqueous solution, it has hardly begun to build a satisfactory theoretical description of the process that has a wide range of practical applica- bility. In such a situation, medicinal chemists try to model this interaction using a physicochemical sents nonregiospecific dispersive and electrostatic forces and the consequent entropic faco o ligand property which closely parallels hydrophobicity, namely, the partition coefficient of the molecules between water and a nonpolar solvent(usually n-octanol ). This property in fact repr For many years, the rational design of novel compounds with therapeutic activity was largely based on the use of free energy expressions and regression analysis techniques(Qsar)to relate structural and physicochemical properties of a set of compounds to their activities or affini ties at a given binding site. Among other properties, octanol/water partition coefficients led to suc cessful correlations in a variety of fields related to pharmacokinetics and drug design The importance of the partition coefficient as a parameter for drug design is due to its rele- vance to a number of steps in the pathway between the administration of a drug and its biologica endpoint such as the drug transport process( Subcellular Pharmacokinetic according to Balaz). Un derstanding the kinetics of ADMET (Administration, Distribution, Toxicity, Excretion and Toxicity) in terms of drug structure and properties is a key step for rational drug development. More-over, log P is the only readily accessible physicochemical property that can be related to the entropic change that accompanies the interaction between a drug and a receptor, which in most cases is the dehydration process that precedes it. Finally, it can also serve as a measure of the interaction be- tween the drug and the recept Log p is a property exceedingly difficult to measure in the real world. The issue becomes even more complicated if the measurements were done at a pH such that the log P had to be cor- rected for ionization. pKa values vary as much as log Ps, if not more: they are sometimes very tem- erature-sensitive. Log D values measured at the same ph but in different laboratories often vary widely. Another problem concerns compounds that can tautomerize or equilibrate between zwitte- rion and neutral form. Experimental values jump all over, especially for compounds with high log P(usually because of solubility issues, micelle formation, and a troublesome tendency of some <www.iupac.org/publications/cd/medicinalchemistry/>1 EXERCISE II.4 COMPARING LOG P CALCULATIONS BY THE GHOSE–CRIPPEN AND VILLAR METHODS Laura Giurato and Salvatore Guccione Department of Pharmaceutical Sciences, University of Catania, viale Andrea Doria 6, Ed. 2 Città Universitaria, I-95125 Catania, Italy Phone: +39 095 738-4020; Fax: +39 095 443604; E-mail: edufarm@unict.it (LG); guccione@unict.it (SG) Scientific computation is not an end itself. It must be implemented in the context of problems to be solved. Introduction Biological activity is not an invariant property of a geometrical arrangement of a subset of ligand atoms, but it is contingent on parameters of the whole molecule and on interactions external to the molecules themselves, i.e., with the receptor. There are three major forces that are important in biochemical ligand binding: hydrophobic, dispersive, and electrostatic interactions. Molar refractivity is related to dispersive forces, and the molecular orbital charge distribution or the electrostatic potential at the van der Waals radius may be used for modeling the electrostatic interaction. However, the hydrophobic interaction, although probably the most important factor for biochemical interaction, is least understood. The term “hy￾drophobic interaction” refers to the force or the corresponding energy that operates between two or more nonpolar solutes in liquid water. Although the theoretical work on hydrophobic interactions led to a clear understanding of the molecular structure of aqueous solution, it has hardly begun to build a satisfactory theoretical description of the process that has a wide range of practical applica￾bility. In such a situation, medicinal chemists try to model this interaction using a physicochemical property which closely parallels hydrophobicity, namely, the partition coefficient of the ligand molecules between water and a nonpolar solvent (usually n-octanol). This property in fact repre￾sents nonregiospecific dispersive and electrostatic forces and the consequent entropic factor. For many years, the rational design of novel compounds with therapeutic activity was largely based on the use of free energy expressions and regression analysis techniques (QSAR) to relate structural and physicochemical properties of a set of compounds to their activities or affini￾ties at a given binding site. Among other properties, octanol/water partition coefficients led to suc￾cessful correlations in a variety of fields related to pharmacokinetics and drug design. The importance of the partition coefficient as a parameter for drug design is due to its rele￾vance to a number of steps in the pathway between the administration of a drug and its biological endpoint such as the drug transport process (Subcellular Pharmacokinetic according to Balaz). Un￾derstanding the kinetics of ADMET (Administration, Distribution, Toxicity, Excretion and Toxicity) in terms of drug structure and properties is a key step for rational drug development. More-over, log P is the only readily accessible physicochemical property that can be related to the entropic change that accompanies the interaction between a drug and a receptor, which in most cases is the dehydration process that precedes it. Finally, it can also serve as a measure of the interaction be￾tween the drug and the receptor. Log P is a property exceedingly difficult to measure in the real world. The issue becomes even more complicated if the measurements were done at a pH such that the log P had to be cor￾rected for ionization. pKa values vary as much as log Ps, if not more: they are sometimes very tem￾perature-sensitive. Log D values measured at the same pH but in different laboratories often vary widely. Another problem concerns compounds that can tautomerize or equilibrate between zwitte￾rion and neutral form. Experimental values jump all over, especially for compounds with high log P (usually because of solubility issues, micelle formation, and a troublesome tendency of some <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006