This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.
Support for this project was provided by the National Science Foundation, Air Force Office of Scientific Research, Department of Energy, Army Research Office, and Ciba-Geigy Corporation.
Library of Congress Catalog Card Number 95-68040
International Standard Book Number 0-309-05097-9
Copyright 1995 by the National Academy of Sciences. All rights reserved.
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COVER ILLUSTRATION: The catalytic binding site of the enzyme purine nucleoside phosphorylase, which plays a key role in immune function, is shown in gray as a space-filling model. An inhibitor of the enzyme is shown in white. A tight fit betwee n the enzyme and the inhibitor is required for binding and inhibitory activity, and a goal of structure-based drug discovery is the design of inhibitors that are geometrically (and chemically) complementary to an enzyme binding site.
The figure was computer generated and resulted from a study that involved calculating geometries of potential inhibitors "docked" in the enzyme binding site (Montgomery et al., 1993). The study involved energy minimization and Monte Carlo-like conformati onal searching using the MacroModel computational chemistry software (Mohamadi et al., 1990). Such a computationally intensive task could not have been carried out 10 years ago and was an integral part of a structure-based drug design effort (Montgomery, 1993; see also Bugg et al., 1993).
Figure courtesy of W. Guida, Pharmaceuticals Division, Ciba-Geigy Corporation.
References
Bugg, C.E., W.M. Carson, and J.A. Montgomery, 1993, Drugs by design, Scientific American 269:92-98.
Mohamadi, F., N.G.J. Richards, W.C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T. Hendrickson, and W.C. Still, 1990, MacroModel--An integrated software system for modeling organic and bioorganic molecules using molecular mechanics, J. Comput . Chem. 11:440-467.
Montgomery, J.A., 1993, Purine nucleoside phosphorylase: A target for drug design, Medicinal Research Reviews 13:209-228.
Montgomery, J.A., S. Niwas, J.D. Rose, J.A. Secrist, Y.S. Babu, C.E. Bugg, M.D. Erion, W.C. Guida, and S.E. Ealick, 1993, Structure-based design of inhibitors of purine nucleoside phosphorylase 1. 9-(arylmethyl) derivatives of 9-deazaguanine, J. Med. Chem. 36:55-69.
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