version date: 1 December 2006 △G°=-00018HSpL-39041 withr=0.68 and Se=2. 33 kcal/mol This general relationship could be used to predict the behavior of any potential ligand, not belonging to a specific class of inhibitors △△ ● penicillopepsin HIV-1 protease 口 others E° 么 10 ▲ bovine thrombin 18◆ adipocyte Lb-p bovine trypsin 2000 3000 4000 5000 6000 Hint score units ig. 4 Plot of experimental AG vS. HINT score units, for a set of 93 different crystallographic protein-ligand complexes 2. CONSERVED WATER MOLECULES IN PROTEIN-LIGAND INTERACTIONS It is well known that water molecules play a very significant role in biological recognition and interactions, exploiting its bridging properties, between proteins and ligands, proteins and proteins and proteins and nucleic acids [37]. Water can act directly, in water-mediated hydrogen bonds and indirectly, in ligand, protein desolvation and hydrophobic interactions [37] The hint force field has been used to evaluate the role of conserved water molecules, through he same rapid protocol used to estimate protein-ligand interactions. Since water is integral in log Po/w, salvation/desolvation and hydrophobic effects, the solvent bulk effects are implicitly encoded in the HINT parameters, but the constrained individual solvent molecules, bridging protein an ligand associations, must be explicitly considered and evaluated Thus, the global hint score for a complex interaction mediated by water molecules is given by two different contributions HSTOTAL=HSprotein-ligand+ HSligand-water [ HSprotein-waterI If we assume that all the bridging interface-placed water molecules are pre-existing, and contribute to define the geometry and the chemical nature of the binding pocket, the latter protein <www.iupac.org/publications/cd/medicinalchemistry/>12 ∆G° = –0.0018 HSP-L –3.9041 with R = 0.68 and SE = 2.33 kcal/mol. This general relationship could be used to predict the behavior of any potential ligand, not belonging to a specific class of inhibitors. Fig. 4 Plot of experimental ∆G° vs. HINT score units, for a set of 93 different crystallographic protein–ligand complexes 2. CONSERVED WATER MOLECULES IN PROTEIN–LIGAND INTERACTIONS It is well known that water molecules play a very significant role in biological recognition and interactions, exploiting its bridging properties, between proteins and ligands, proteins and proteins and proteins and nucleic acids [37]. Water can act directly, in water-mediated hydrogen bonds and, indirectly, in ligand, protein desolvation and hydrophobic interactions [37]. The HINT force field has been used to evaluate the role of conserved water molecules, through the same rapid protocol used to estimate protein–ligand interactions. Since water is integral in log Po/w, salvation/desolvation and hydrophobic effects, the solvent bulk effects are implicitly encoded in the HINT parameters, but the constrained individual solvent molecules, bridging protein and ligand associations, must be explicitly considered and evaluated. Thus, the global HINT score for a complex interaction mediated by water molecules is given by two different contributions: HSTOTAL = HSprotein-ligand + HSligand-water [+ HSprotein-water] If we assume that all the bridging interface-placed water molecules are pre-existing, and contribute to define the geometry and the chemical nature of the binding pocket, the latter protein￾Hint Score units 0 1000 2000 3000 4000 5000 6000 ∆G° (Kcal/mol) -18 -14 -10 -6 -2 bovine thrombin human thrombin hydroxynitrile lyase adipocyte l.b.p. retinol b.p. bovine trypsin tryptophan synthase penicillopepsin saccharopepsin HIV-1 protease others <www.iupac.org/publications/cd/medicinal_chemistry/> version date: 1 December 2006