期刊
JOURNAL OF COMPUTATIONAL CHEMISTRY
卷 33, 期 6, 页码 607-616出版社
WILEY
DOI: 10.1002/jcc.21983
关键词
uPA; urokinase; molecular dynamics; hybrid methods; QM; MM; MM; PBSA; (QM; MM)PBSA; free energy of binding; Hydrogen bond; atomic charges variations
资金
- CINES (Centre Informatique National de l'Enseignement Superieur, France) [2009072208]
Urokinase plasminogen activator (uPA) is an enzyme involved in cancer growth and metastasis. Therefore, the design of inhibitors of uPA is of high therapeutic value, and several chemical families have been explored, even if none has still emerged, emphasizing the need of a rationalized approach. This work represents a complete computational study of uPA complexed with five inhibitors, which present weak similarities. Molecular dynamics simulations in explicit solvent were conducted, and structural analyses, along with molecular mechanics (MM)/PoissonBoltzmann surface area free energies estimations, yield precious structureactivity relationships of these inhibitors. Besides, we realized supplemental QM/MM computations that improved drastically the quality of our models providing original information on the hydrogen bonds and charge transfer effects, which are, most often, neglected in other studies. We suggest that these simulations and analyses could be reproduced for other systems involving protein/ligand molecular recognitions. (C) 2012 Wiley Periodicals, Inc. J Comput Chem, 2012
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