Free energy perturbation studies on binding of A-74704 and its diester analog to HIV-1 protease.
Free energy simulations have been employed to rationalize the binding differences between A-74704, a pseudo C2-symmetric inhibitor of HIV-1 protease and its diester analog. The diester analog inhibitor, which misses two hydrogen bonds with the enzyme active site, is surprisingly only 10-fold weaker. The calculated free energy difference of 1.7 +/- 0.6 kcal/mol is in agreement with the experimental result. Further, the simulations show that such a small difference in binding free energies is due to (1) weaker hydrogen bond interactions between the two (P1 and P1') NH groups of A-74704 with Gly27/Gly27' carbonyls of the enzyme and (2) the higher desolvation free energy of A-74704 compared with its ester analog. The results of these calculations and their implications for design of HIV-1 protease inhibitors are discussed.
Vertex Pharmaceuticals Incorporated, Cambridge, MA 02139, USA.
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Murcko
D001665:Binding Sites; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D015394:Molecular Structure; D015202:Protein Engineering; D013402:Sugar Alcohols / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D017320:HIV Protease Inhibitors; D013402:Sugar Alcohols; C065300:A 74704; D016333:HIV Protease; D014633:Valine