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Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors
Author(s) -
Barbault Florent,
Maurel François
Publication year - 2012
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.21983
Subject(s) - molecular dynamics , molecular mechanics , hydrogen bond , chemistry , urokinase , qm/mm , computation , activator (genetics) , computational chemistry , molecule , computer science , biochemistry , biology , gene , organic chemistry , algorithm , genetics
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)/Poisson–Boltzmann surface area free energies estimations, yield precious structure–activity 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. © 2012 Wiley Periodicals, Inc. J Comput Chem, 2012