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Cynthia Dias Selassie and Teri E. Klein

Department of Chemistry
Pomona College, Claremont

Computer Graphics Laboratory University of California, San Francisco

  Image of DHFR

We are interested in the study of ligand-receptor interactions in order to clearly delineate the different molecular forces involved in binding interactions and the molecular recognition process. This work has focused primarily on well-characterized enzymatic receptors such as dihydrofolate reductase (see image above), trypsin, chymotrypsin, thiopurine N-methyl transferase and elastase and their corresponding inhibitors and/or substrates. These research activities focus on understanding basic perturbations at the molecular level via utilization of the Quantitative Structure-Activity Relationship (QSAR) paradigm in the design and synthesis of more effective chemotherapeutic agents.

Simple model systems, as exemplified by the interactions of the X-phenyl esters of N-benzoyl glycine with well-characterized enzymes such as the serine protease porcine pancreatic elastase, allow us to examine the intermolecular force involved in the hydrolysis of these substrates. Comparisons of QSAR's and molecular graphics obtained with those from other serine proteases serve to support the commonality in mechanistic features. This approach also aids in identifying the physiochemical attributes of the surfaces and crevices involved in binding at the active site. Information garnered in this manner is useful in shedding light on the binding sites of enzymes and membrane-bound receptors.

Acknowledgments: This research is supported by the National Institutes of Health, Division of Environmental Sciences, grant ES07595 (C.R. Selassie, P.I.) and the National Center for Research Resources, grant P41-RR01081 (T.E. Ferrin, P.I.).

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