version date: 1 December 2006 implicitly enclose hydrophobic and solvation/desolvation effects, directly related to the entropic contribution involved in molecular associations. The formation of a complex between a protein and a ligand in aqueous solution can be represented by the following equilibrium 2a+La已PLa where P is the protein, L the ligand, P'l' the new complex, and k+1 and k-l are, respectively, the association and dissociation constants Both Ka(association)and Ka(dissociation) are related to the activity of the reacting species n, but, if extremely dilute solutions are considered, activities can be substituted by concentrations. Starting from the constant values it is possible to calculate the free energy of binding associated to the binding event, using the following relation △G°=- RTIn Kd T is the absolute temperature, R the gas constant and Ago the binding free energy variation measured in standard condition(298%K, I atm, and I M concentration for Po/w is also an equilibrium constant for solute transfer between octanol and water log Po/w=-△AG/2.303RT where r and t are constants It derives that log pol=k△G° where k =-0733 kcal mol-I at 298 K Because ∑a;= log pol is obvious the relationship between hydrophobic atomic constants ai and AG, thus, including both enthalpic and entropic contribution [ 9] HINT can be defined as a natural and intuitive force field, able to estimate, using experimentally determined log P values, not only the enthalpic but also the entropic effects included in noncovalent interactions, like hydrogen bonding, Coulombic forces, acid-base and hydrophobic contact Hydrophobic and polar contacts, both identified as hydropathic interactions, are strictly related to solvent partitioning phenomena. In fact, the solubilization of a ligand in a mixed solvent system, <www.iupac.org/publications/cd/medicinal_chemistry/>6 implicitly enclose hydrophobic and solvation/desolvation effects, directly related to the entropic contribution involved in molecular associations. The formation of a complex between a protein and a ligand in aqueous solution can be represented by the following equilibrium: Paq. + Laq. ⇄ P'L'aq.' where P is the protein, L the ligand, P'L' the new complex, and k+1 and k–1 are, respectively, the association and dissociation constants. Ka = Kd –1 = [ ] [ ][ ] P L PL Both Ka (association) and Kd (dissociation) are related to the activity of the reacting species n, but, if extremely dilute solutions are considered, activities can be substituted by concentrations. Starting from the constant values it is possible to calculate the free energy of binding associated to the binding event, using the following relation: ∆G° = –RT ln Kd T is the absolute temperature, R the gas constant and ∆G° the binding free energy variation measured in standard condition (298 °K, 1 atm, and 1 M concentration for both reagents and products). Po/w is also an equilibrium constant for solute transfer between octanol and water: log Po/w = –∆G°/2.303 RT where R and T are constants. It derives that log Po/w = k ∆G° where k ≈ –0.733 kcal mol–1 at 298 K. Because Σai = log Po/w it is obvious the relationship between hydrophobic atomic constants ai and ∆G°, thus, including both enthalpic and entropic contribution [9]. HINT can be defined as a natural and intuitive force field, able to estimate, using experimentally determined log P values, not only the enthalpic but also the entropic effects included in noncovalent interactions, like hydrogen bonding, Coulombic forces, acid-base and hydrophobic contacts. Hydrophobic and polar contacts, both identified as hydropathic interactions, are strictly related to solvent partitioning phenomena. In fact, the solubilization of a ligand in a mixed solvent system, k+1 k-1 <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006