Development of proteo-chemometrics: a novel technology for the analysis ofdrug-receptor interactions

A novel method for the analysis of drug receptor interactions has been deve loped and used to explore mechanisms involved in the binding of 4-piperidyl oxazole antagonists to alpha (1a)-, alpha (1b)- and alpha (1d)-adrenocepto rs. The method exploits affinity data for a series of organic chemical comp ounds binding to wild-type and artificially mutated receptors. The receptor sequences and compounds are assigned predictor variables that are correlat ed to the measured pharmacological activities using partial least-squares p rojections to latent structures. The predictor variables consist of one des criptor block derived from the chemical properties of the receptors' primar y amino acid sequences and another descriptor block derived from the chemic al properties of the organic compounds. The cross-terms generated from the two descriptor blocks are also derived. Using this approach, very sturdy mo dels were generated describing the interactions of the chemical compounds w ith the receptors. Models are useful to predict binding affinity and recept or subtype selectivity of compounds prior to their synthesis, and may find use in rational drug design. Moreover, models also give quantitative inform ation about the interactions of the amino acids of the receptors with the l igands, thereby giving an insight into the molecular mechanisms' involved i n ligand binding. (C) 2001 Elsevier Science B.V. All rights reserved.