Thermodynamic Cycle-Perturbation Approach M
Proc. Natl. Acad. Sci. USA Vol. 88, pp. 10287-10291, November 1991 Biophysics Relative differences in the binding free energies of human immunodeficiency virus 1 protease inhibitors: A thermodynamic cycle-perturbation approach M. RAMI REDDYt*, VELLARKAD N. VISWANADHANt§, AND JOHN N. WEINSTEIN§ tAgouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, CA 92121; and 1National Cancer Institute, Laboratory of Mathematical Biology, Building 10, Room 4B-56, National Institutes of Health, Bethesda, MD 20892 Communicated by Robert G. Parr, August 12, 1991 ABSTRACT Peptidomimetic inhibitors of the human im- personal communication) and its analogs, binding constants munodeficiency virus 1 protease show considerable promise for are also available (8, 9). This presents us with an opportunity treatment of AIDS. We have, therefore, been seeking comput- to perform free-energy simulations that might aid in system- er-assisted drug design methods to aid in the systematic design atic design of peptide-based HIV-1-PR inhibitors. of such inhibitors from a lead compound. Here we report Free-energy simulation techniques have been used to thermodynamic cycle-perturbation calculations (using molec- probe a variety ofchemical and biochemical factors including ular dynamics simulations) to compute the relative difference solvation and binding of ions and small molecules (10, 11), in free energy of binding that results when one entire residue relative binding free-energy differences between similar in- (valine) is deleted from one such inhibitor. In
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