version date: 1 December 2006 like water and octanol, involves the same processes and atom-atom interactions as biomolecular interactions within or between proteins and ligands [24]. The program was designed to consider and investigate hydrophobicity and hydropathic interactions in several biological areas. HINT is able to (i calculate hydrophobic atomic constant for each atom in small molecule or even in macromolecule and quantitatively score molecular interactions, (ii) create hydrophobic maps or fields for small molecules in protein environments, (iii) map the hydrophobic and polar nature of the surrounding receptor from the structure of small interacting molecules, providing a hydrophobic interaction template for the definition of secondary and tertiary protein structure, and (iv)suggest modes of inter-helix interactions in trans-membrane ion channel [25]. All these features and capabilities make hinT a suitable tool, not only for the study of single and simple interactions, but also for the virtual screening of organic libraries and for structure-based drug design interactions between atom-atom couples are calculated using the following equation bj=ai Sia s Ti ri+ry where bi represents the interaction score between atoms i and j, a is the hydrophobic atomic constant, S is the SASA, Ti is a logic function assuming-l or +l value, depending on the character of the interacting polar atoms, while Ri and ri are a function of the distance between atoms i and The whole interaction between two molecules, like protein and ligand, or protein and DNA, can be represented as ΣΣb=Ea1 Siai si tii r+r bj>0 identifies favorable interactions, while bi<0 the unfavorable ones. Interactions can be divided into: polar-polar, hydrophobic-hydrophobic, and hydrophobic-polar. While hydrophobic hydrophobic contacts are always positively scored, polar interactions, depending on the charge of interacting groups can be favorable(acid-base), or unfavorable (acid-acid and base-base) Hydrophobic-polar contacts are constantly negatively scored by HINT, so they negatively contribute to the global binding energy. The Hint hydrophobic-polar interaction score term represents an empirical free-energy evaluation for the energy cost to desolate the polar regions of proteins or ligands, placing them in a hydrophobic environment The HINT software allows us to reduce the information from bulk molecule solvent partitioning, to discrete interactions between biological molecules, i.e., ligand-protein, protein-protein, protein- DNA, and protein-ligand-water Small differences have been revealed in hydrophobicity estimations between HINT and CLOGP Some examples are reported in Table 1 [25] <www.iupac.org/publications/cd/medicinal_chemistry/>7 like water and octanol, involves the same processes and atom–atom interactions as biomolecular interactions within or between proteins and ligands [24]. The program was designed to consider and investigate hydrophobicity and hydropathic interactions in several biological areas. HINT is able to (i) calculate hydrophobic atomic constant for each atom in small molecule or even in macromolecule and quantitatively score molecular interactions, (ii) create hydrophobic maps or fields for small molecules in protein environments, (iii) map the hydrophobic and polar nature of the surrounding receptor from the structure of small interacting molecules, providing a hydrophobic interaction template for the definition of secondary and tertiary protein structure, and (iv) suggest modes of inter-helix interactions in trans-membrane ion channel [25]. All these features and capabilities make HINT a suitable tool, not only for the study of single and simple interactions, but also for the virtual screening of organic libraries and for structure-based drug design. Interactions between atom–atom couples are calculated using the following equation: bij = ai Si aj Sj Tij Rij + rij where bij represents the interaction score between atoms i and j, a is the hydrophobic atomic constant, S is the SASA, Tij is a logic function assuming –1 or +1 value, depending on the character of the interacting polar atoms, while Rij and rij are a function of the distance between atoms i and j. The whole interaction between two molecules, like protein and ligand, or protein and DNA, can be represented as ΣΣ bij = ΣΣ ai Si aj Sj Tij Rij + rij bij > 0 identifies favorable interactions, while bij < 0 the unfavorable ones. Interactions can be divided into: polar–polar, hydrophobic–hydrophobic, and hydrophobic–polar. While hydrophobic– hydrophobic contacts are always positively scored, polar interactions, depending on the charge of interacting groups can be favorable (acid–base), or unfavorable (acid–acid and base–base). Hydrophobic–polar contacts are constantly negatively scored by HINT, so they negatively contribute to the global binding energy. The HINT hydrophobic–polar interaction score term represents an empirical free-energy evaluation for the energy cost to desolvate the polar regions of proteins or ligands, placing them in a hydrophobic environment. The HINT software allows us to reduce the information from bulk molecule solvent partitioning, to discrete interactions between biological molecules, i.e., ligand–protein, protein–protein, protein– DNA, and protein–ligand–water. Small differences have been revealed in hydrophobicity estimations between HINT and CLOGP. Some examples are reported in Table 1 [25]. <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006