Abstract

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. One a pharmacophore consistent with the entire set of compouns is obtained, then it will be used to map receptor sites. Development of this approach conceptually as well as algorithmically is a primary objective. The processing through multiarray processors as a prologue to VLSI implementation. Alternative formulations of the problem by distance geometry will also be explored. This approach will be applied to isolated enzyme systems which transform steroids, or synthesize S-adenosylmethionine. Dopamine and other biogenic amines receptors will be examined to probe receptor heterogenity. The receptor-bound conformation of peptide hormones, i.e. angiotensin, thyroliberin, bradykinin and enkephalin, will be determined through the introduction synthetically of conformational constraints and their conformational analysis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM024483-11
Application #
3096071
Study Section
Pharmacology-Toxicology Review Committee (PTR)
Project Start
1978-12-01
Project End
1990-11-30
Budget Start
1988-12-01
Budget End
1990-11-30
Support Year
11
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Huang, E S; Samudrala, R; Ponder, J W (1998) Distance geometry generates native-like folds for small helical proteins using the consensus distances of predicted protein structures. Protein Sci 7:1998-2003
Huang, E S; Koehl, P; Levitt, M et al. (1998) Accuracy of side-chain prediction upon near-native protein backbones generated by Ab initio folding methods. Proteins 33:204-17
Hodsdon, M E; Ponder, J W; Cistola, D P (1996) The NMR solution structure of intestinal fatty acid-binding protein complexed with palmitate: application of a novel distance geometry algorithm. J Mol Biol 264:585-602
Rutledge, L D; Perlman, J H; Gershengorn, M C et al. (1996) Conformationally restricted TRH analogs: a probe for the pyroglutamate region. J Med Chem 39:1571-4
Zhang, W J; Nikiforovich, G V; Perodin, J et al. (1996) Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: conformational and biological implications. J Med Chem 39:2738-44
Dammkoehler, R A; Karasek, S F; Shands, E F et al. (1995) Sampling conformational hyperspace: techniques for improving completeness. J Comput Aided Mol Des 9:491-9
Beusen, D D; Zabrocki, J; Slomczynska, U et al. (1995) Conformational mimicry: synthesis and solution conformation of a cyclic somatostatin hexapeptide containing a tetrazole cis amide bond surrogate. Biopolymers 36:181-200
Vakser, I A (1995) Protein docking for low-resolution structures. Protein Eng 8:371-7
Nikiforovich, G V; Kolodziej, S A; Nock, B et al. (1995) Conformationally readdressed CCK-B/delta-opioid peptide ligands. Biopolymers 36:439-52
Ho, C M; Marshall, G R (1995) DBMAKER: a set of programs to generate three-dimensional databases based upon user-specified criteria. J Comput Aided Mol Des 9:65-86

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