QUASI-ATOMISTIC RECEPTOR SURFACE MODELS - A BRIDGE BETWEEN 3-D QSAR AND RECEPTOR MODELING

A ''quasi-atomistic receptor model'' refers to a three-dimensional rec eptor surface, populated with atomistic properties (hydrogen bonds, sa lt bridges, hydrophobic particles, and solvent) mapped onto it. In con trast to other 3D-QSAR approaches, an algorithm developed at our labor atory allows for the adaptation of the receptor-surface defining envel ope to the topology of the individual ligand molecules. In addition, i t includes H-bond flip-flop particles which can simultaneously act as H-bond donors and H-bond accepters toward different ligand molecules, binding to the surrogate within a pharmacophore hypothesis. Such parti cles mimic aminoacid residues able to engage in differently directed H -bonds at the true biological receptor. Ligand-receptor interaction en ergies are evaluated using a directional force field for hydrogen bond s and salt bridges. On the basis of a series of ligand molecules with individually adapted receptor envelopes, the software Quasar allows a family of receptor models to be generated using a genetic algorithm co mbined with cross-validation. Our concept has been used to derive semi quantitative structure-activity relationships for the beta 2-adrenergi c, aryl hydrocarbon, cannabinoid, neurokinin-1, and sweet-taste recept or as well as for the enzyme carbonic anhydrase. The receptor surrogat es for these systems are able to predict free energies of ligand bindi ng for independent sets of test ligand molecules within 0.4-0.8 kcal/m ol (RMS) of the experimental value.