FURTHER DEVELOPMENT OF HYDROGEN-BOND FUNCTIONS FOR USE IN DETERMINING ENERGETICALLY FAVORABLE BINDING-SITES ON MOLECULES OF KNOWN STRUCTURE .2. LIGAND PROBE GROUPS WITH THE ABILITY TO FORM MORE THAN 2 HYDROGEN-BONDS

The specificity of interactions between biological macromolecules and their ligands may be partially attributed to the directional properties of hydrogen bonds. We have now extended the GRID method (Goodford, P. J. J. Med. Chem. 1985, 28, 849. Boobbyer, D. N. A.; Goodford, P. J.; McWhinnie, P. M.; Wade, R. C. J. Med. Chem. 1989, 32, 1083). of determining energetically favorable ligand binding sites on molecules of known structure, in order to improve the treatment of groups which can make multiple hydrogen bonds. In this method, the interaction energy between a probe (a small chemical group that may be part of a larger ligand) and a target molecule is calculated using an energy function which includes a hydrogen bond term which is dependent on the length of the hydrogen bond, its orientation at the hydrogen-bonding atoms, and their chemical character. The methods described in the preceding paper (Wade, R. C.; Clark, K. J.; Goodford, P. J. J. Med. Chem., preceding paper in this issue) for probes capable of making two hydrogen bonds are here extended to the following probes which have the ability to make more than two hydrogen bonds: ammonium -NH3+, amine -NH2, sp3-hybridized hydroxyl, and water. Use of the improved GRID procedure is demonstrated by the determination of the conformation of an amino acid side chain at the subunit interface in hemoglobin and of the location of water binding sites in human lysozyme.