Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 132, Issue 10, Pages 3312-3320Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja9059156
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Funding
- GENCI (CINES/IDRIS) [2009-075009]
- Centre de Ressources Informatiques de Haute Normandie (CRIHAN, Rouen)
- CCRE (UPMC, Paris, France)
- Ligue Nationale contre le Cancer, Equipe Labellisee [U648]
- French National Research Agency (ANR)
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Using polarizable molecular mechanics (PMM), we have compared the complexation energies of the focal adhesion kinase (FAK) kinase by five inhibitors in the pyrrolopyrimidine series. These inhibitors only differ by the substitution position of a carboxylate group on their benzene or pyridine rings, and/or the length of the connecting (CH2)(n) chain (n = 0-2) while their inhibitory properties vary from micromolar to nanomolar. Energy balances in which solvation/desolvation effects are computed by a continuum reaction field procedure failed to rank the inhibitors according to their inhibitory potencies. In marked contrast, including energy-minimizing in the protein inhibitor binding site limited numbers of structural water molecules, namely five to seven, ranked these energy balances conforming to the experimental ordering. The polarization energy contribution was the most critical energy contribution that stabilized the best-bound inhibitor over the others. These results imply that (a) upon docking charged inhibitors into the active site of kinases such as FAK, the presence of a limited number of structured water molecules is critical to enable meaningful relative energy balances and (b) accounting for an explicit polarization contribution within Delta E is indispensable.
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