version date: 1 December 2006 EXERCISE 12 HYDROPHOBICITY IN DRUG DESIGN Pietro Cozzini and francesca Spyrakis Laboratory of Molecular Modelling, Department of General and Inorganic Chemistry, Chemical-Physics and Analytical Chemistry, University of Parma 43100 Parma, Italy, Department of Biochemistry and Molecular Biology, University of Parma, 43100 Parma, Italy Hydrophobicity represents the tendency of a substance to repel water and to avoid the complete dissolution in water. The term"hydrophobic"means"water fearing,, from the Greek words hydro water,and phobo, fear. Being that hydrophobicity is one of the most important physicochemical parameters associated with chemical compounds, several studies have been carried out to understand, evaluate, and predict this parameter [1-8]. In fact, hydrophobicity governs numerous and different biological processes, such as, for example, transport, distribution, and metabolism of biological molecules; molecular recognition; and protein folding. Therefore, the knowledge of a parameter that describes the behavior of solutes into polar and nonpolar phases is essential to predict the transport and activity of drugs, pesticides, and xenobiotic The hydrophobic effect can be defined as" the tendency of nonpolar groups to cluster, shielding themselves from contact with an aqueous environment". The hydrophobic effect in proteins can also be described as the tendency of polar species to congregate in such a manner to maximize electrostatic interactions. Proteins, in fact, organize themselves to expose polar side-chains toward the solvent, and retain hydrophobic amino acid in a central hydrophobic core. The hydrophobic effect constitutes one of the main determinants of globular protein molecules structure and folding The hydrophilic regions tend to surround hydrophobic areas, which gather into the central hydrophobic core, generating a protein characterized by a specific and function-related three- dimensional structure. This driving force not only guides protein folding processes, but also any kind of biological interaction. Biological molecules interact, mainly, via electrostatic forces including hydrogen bonds or hydrogen-bonding networks, often formed through water molecules During a protein-ligand association, water molecules not able to properly locate themselves at the complex interface, are displaced and pushed into the bulk solvent, increasing entropy. Thus, it is possible to define the hydrophobic effect as a free energy phenomenon, constituted by both <ww.iupac. org/publications/cd/medicinal chemistry/>1 EXERCISE I.12 HYDROPHOBICITY IN DRUG DESIGN Pietro Cozzini1 and Francesca Spyrakis2 1 Laboratory of Molecular Modelling, Department of General and Inorganic Chemistry, Chemical-Physics and Analytical Chemistry, University of Parma, 43100 Parma, Italy; 2 Department of Biochemistry and Molecular Biology, University of Parma, 43100 Parma, Italy Hydrophobicity represents the tendency of a substance to repel water and to avoid the complete dissolution in water. The term “hydrophobic” means “water fearing”, from the Greek words hydro, water, and phobo, fear. Being that hydrophobicity is one of the most important physicochemical parameters associated with chemical compounds, several studies have been carried out to understand, evaluate, and predict this parameter [1–8]. In fact, hydrophobicity governs numerous and different biological processes, such as, for example, transport, distribution, and metabolism of biological molecules; molecular recognition; and protein folding. Therefore, the knowledge of a parameter that describes the behavior of solutes into polar and nonpolar phases is essential to predict the transport and activity of drugs, pesticides, and xenobiotics. The hydrophobic effect can be defined as “the tendency of nonpolar groups to cluster, shielding themselves from contact with an aqueous environment”. The hydrophobic effect in proteins can also be described as the tendency of polar species to congregate in such a manner to maximize electrostatic interactions. Proteins, in fact, organize themselves to expose polar side-chains toward the solvent, and retain hydrophobic amino acid in a central hydrophobic core. The hydrophobic effect constitutes one of the main determinants of globular protein molecules structure and folding: The hydrophilic regions tend to surround hydrophobic areas, which gather into the central hydrophobic core, generating a protein characterized by a specific and function-related three￾dimensional structure. This driving force not only guides protein folding processes, but also any kind of biological interaction. Biological molecules interact, mainly, via electrostatic forces, including hydrogen bonds or hydrogen-bonding networks, often formed through water molecules. During a protein-ligand association, water molecules not able to properly locate themselves at the complex interface, are displaced and pushed into the bulk solvent, increasing entropy. Thus, it is possible to define the hydrophobic effect as a free energy phenomenon, constituted by both <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006