title: Is inhibition process better described with MD(QM/MM) simulations? The case of urokinase type plasminogen activator inhibitors.
abstract: 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.
authors.affiliation: Univ Paris Diderot, Sorbonne Paris Cité, ITODYS, UMR CNRS 7086, 15 rue J-A de Baïf, 75205 Paris Cedex 13, France. florent.barbault@univ-paris-diderot.fr
authors.forename: Florent
authors.initials: F
authors.lastname: Barbault
authors.forename: François
authors.initials: F
authors.lastname: Maurel
mesh_terms: D003198:Computer Simulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D015394:Molecular Structure; D011789:Quantum Theory; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D014568:Urokinase-Type Plasminogen Activator