The objective of this program project is an integrated multidisciplinary approach to drug design. In particular, the concept of pharmacophore will be tested in a variety of systems by systematic examination of its consequences through the Active Analog Approach. Exhaustive innumeration of possible orientations of candidate functional groups for the pharmacophore will be examined in series of active compounds. Once a pharmacophore, or active site model, consistent with the entire set of compounds is obtained, then it will be used to map receptor sites. Development of this approach, both conceptually and algorithmically, is a primary objective. Quantitative criteria for distinguishing between alternative hypotheses will be used based on 3D QSAR methodology such as CoMFA. The computational complexity of exhaustive search requires development of parallel processing through multiarray processors. Alternative formulations of the problem by distance geometry will also be explored. The receptor-bound conformation of peptide hormones, such as angiotensin, bradykinin, thyroliberin, and morphiceptin will be studied. Larger macromolecular systems such as enzymes of known structure (thermolysin) and the nicotinic acetylcholine receptor will also be studied. Experimental NMR methods to determine the receptor-bound conformation of ligands will also be explored. This includes both transfer and isotope-directed NOE experiments as well as Rotational Echo Double Resonance (REDOR) NMR spectroscopy, a solid NMR method capable of studying the solid or aggregated state. Modern asymmetric synthetic procedures will be exploited to prepare desired organic compounds which mimic the proposed receptor-bound conformation of thyroliberin and other peptides.
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