Free energy perturbation studies on binding of A-74704 and its diester analog to HIV-1 protease |
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Authors: | Rao, B.G. Murcko, M.A. |
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Affiliation: | Vertex Pharmaceuticals Incorporated 130 Waverly Street, Cambridge, MA 02139, USA |
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Abstract: | Free energy simulations have been employed to rationalize thebinding differences between A-74704, a pseudo C2- symmetricinhibitor of HIV-1 protease and its diester analog. The diesteranalog inhibitor, which misses two hydrogen bonds with the enzymeactive site, is surprisingly only 10-fold weaker. The calculatedfree energy difference of 1.7 ± 0.6 kcal/mol is in agreementwith the experimental result. Further, the simulations showthat such a small difference in binding free energies is dueto (1) weaker hydrogen bond interactions between the two (P1and P1) NH groups of A-74704 with Gly27/Gly27' carbonyls ofthe enzyme and (2) the higher desolvation free energy of A-74704compared with its ester analog. The results of these calculationsand their implications for design of HIV-1 protease inhibitorsare discussed. |
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Keywords: | AMBER/ HIV-1 protease inhibitors/ hydrogen bonding/ molecular dynamics/ solvation |
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