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complexed with various inhibitors offers a unique opportunity for the development of such
computational methods if the structural data can be coupled with thermodynamic measurements of
inhibitor-protein binding. These include direct measurements by microcalorimetry of the association
constant, K, and in addition the enthalpy, entropy, heat capacity, and stoichiometry of binding. The
combination of such thermodynamic and structural data will lead to a more precise understanding of the
factors that influence binding and, ultimately, will lead to new general design principles that can be
applied to drug discovery in the area of AIDS as well as other challenging diseases.
Acknowledgments
I wish to thank all my co-workers from Agouron who contributed to these studies, in particular J.
Davies, S. Reich, M. Melnick, V. Kalish, A. Patick, L. Musick, and B-W. Wu. Steven Kaldor from Ely
Lilly is acknowledged for his contribution in designing AG1343 (nelfinavir). I would like to thank
Richard Ogden for critical reading of the manuscript and D. Olson for expert assistance in preparing the
manuscript.
References
1. Mitsuya H, Yarchoan R Broder S. Molecular Targets for AIDS therapy. Science 1990;
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drug design. Chimica Oggi 1991; 9:6–14.
4. Ding J, Das K, Yadav PNS, Hsiou Y, Zhang W, Hughes SH, Arnold E. Structural studies of HIV-1
reverse transcriptase and implications for drug design. In: Structure-Based Drug Design. New York:
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5. Perno CF, Bergamini A, Pesce CD. Inhibition of the protease of human immunodeficiency virus
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WG. A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation.
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