Murray Goodman

Organic, biophysical and biopolymer chemistry: peptide synthesis; peptidomimetics; conformation; computer-molecular dynamics; spectroscopy; structure-biological activity relationships.

 

Ph.D. University of California, Berkeley, 1953; Research Associate, Massachusetts Institute of Technology, 1953-1955; National Research Council Fellow, Cambridge University, 1955-1956; Appointed to faculty, Polytechnic Institute of Brooklyn, 1956-1970; Editor, Biopolymers, 1963-; Director, Polymer Research Institute, 1967-1970; Appointed to faculty, 1970-.

(858) 534-4466

mgoodman@ucsd.edu

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 A major focus of the research in Professor Goodman's laboratories is on structure-activity relationships of specific hormone agonists and antagonists, opioids, neuropeptides, antibiotics and tastants. Toward this end, an integrated approach has been developed which combines synthesis, spectroscopic studies and computer simulations, as well as biological assays carried out by collaborating laboratories. Target molecules are selected for synthesis through molecular modeling simulations of specific constrained analogs which exhibit strong conformational preferences. Such molecules facilitate both our spectroscopic studies and computer simulations. Constraints are introduced into the molecules by cyclization, the use of peptidomimetics and other steric modifications. The simulations involve flexible geometry energy minimizations. Once the target analogs are designed on the basis of molecular modeling, we undertake the synthesis of these compounds. Syntheses currently underway include enkephalin and somatostatin analogs, peptide derived sweeteners, and drug congeners. Another project involves a set of novel biopolymers to study conformational transitions and their effects on membrane interactions.

Following the synthesis of these molecules, the characterizations of the compounds are carried out under a variety of conditions. Using the most recent one- and two-dimensional NMR, circular dichroism and infrared spectroscopy, molecular conformations are probed in different environments. Utilizing temperature, solvent and concentration studies, these techniques provide information on peptide conformation in solution. The conformational preferences of the analogs obtained from the spectroscopic investigations are then utilized as input for further computer simulations. This includes additional energy minimizations and molecular dynamics that utilize the observed NOE, hydrogen bonds and coupling constants, as constraints. Distance geometry constraints lead to a small perturbation of the potential energy. Conformations from these studies and molecular dynamics are compatible with each other. For most of these biologically active peptides, the results from conformational analysis along with the biological testing are used to develop or propose models for observed biological response. These models are then tested by the design and synthesis of additional analogs that specifically explore one or another structural requirements for bioactivity. In this manner, the approach to the study of structure-activity relationships is a continuous refinement of requirements for biological activity integrating synthesis, spectroscopy, computer simulations, and biological testing.

 

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SELECTED PUBLICATIONS

A Facile Synthesis of Orthogonally Protected Stereoisomeric Lanthionines by Regioselective Ring Opening of Serine -Lactone Derivatives. With H. Shao, S.H.H. Wang, C.W Lee, and G. Osapay. J. Org. Chem. 60, 2956 (1995).

 

Highly Potent Sidechain-Mainchain Cyclized Dermorphin-Deltorphin Analogs: An Integrated Approach Including Synthesis, Bioassays, NMR Spectroscopy and Molecular Modeling. With S. Ro, Q. Zhu, C.-W. Lee, K. Darlak, A.F. Spatola, N.H. Chung, P.W. Schiller, A.B. Malmberg, T.L. Yaksh and T.F. Burks. J. Pep. Sci. 1:3, 157 (1995).

 

Recent Developments in Retro Peptides and Proteins--The On Going Topochemical Exploration. With M. Chorev. Trends in Biotech. 13, 438 (1995).

 

, -Dimethylcyclolanthionines, New Constrained Dipeptide Mimetics: Synthesis, Crystal Structures, and Conformational Studies. With H. Shao, C.-W. Lee, Q. Zhu, and P. Gantzel. Angew. Chemie. 35, 90 (1996).

 

An Enantiomeric Synthesis of allo-Threonines and -Hydroxyvalines. With H. Shao. J. Org. Chem. 61, 2582 (1996).

 

A Template-Induced Incipient Collagen-Like Triple-Helical Structure. With Y. Feng, G. Melacini, and J.P. Taulane. J. Am. Chem. Soc. 118, 5156 (1996).

 

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