Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors
Copyright © 2012 Wiley Periodicals, Inc.
| Publié dans: | Journal of computational chemistry. - 1984. - 33(2012), 6 vom: 05. März, Seite 607-16 |
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| Auteur principal: | |
| Autres auteurs: | |
| Format: | Article en ligne |
| Langue: | English |
| Publié: |
2012
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| Accès à la collection: | Journal of computational chemistry |
| Sujets: | Journal Article Research Support, Non-U.S. Gov't Enzyme Inhibitors Ligands Urokinase-Type Plasminogen Activator EC 3.4.21.73 |
| Résumé: | Copyright © 2012 Wiley Periodicals, Inc. 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 |
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| Description: | Date Completed 29.05.2012 Date Revised 09.02.2012 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.21983 |