PSEUDORECEPTOR MODELING - THE CONSTRUCTION OF 3-DIMENSIONAL RECEPTOR SURROGATES

Pseudoreceptor modeling allows the construction of a receptor surrogat e for a structurally uncharacterized bioregulator (an enzyme or recept or) based on the structures of known ligand molecules. Although, in ge neral, a pseudoreceptor and its natural counterpart will bear little s tructural resemblance, they should accommodate a series of ligand mole cules in a relatively similar binding sense. A pseudoreceptor validate d using a representative series of ligand molecules may subsequently b e used to estimate relative free energies for binding for novel ligand molecules. A pseudoreceptor-modeling concept developed at our laborat ory allows the generation of a three-dimensional peptidic receptor mod el (a miniprotein) about any molecular framework of interest. The conc ept was validated by constructing pseudoreceptors for the enzyme human carbonic anhydrase, the dopaminergic receptor, and the beta(2)-adrene rgic receptor. Predicted differences in free energy of ligand binding toward the pseudoreceptor, Delta(Delta G degrees(calc)), and experimen tal values determined toward the biological receptor, Delta(Delta G de grees(exp)), agree to within 0.6 and 1.2 kcal/mol.