10640
J. Phys. Chem. B 2003, 107, 10640-10652
Modeling of Copper(II) Complexes with the SIBFA Polarizable Molecular Mechanics Procedure. Application to a New Class of HIV-1 Protease Inhibitors Marie Ledecq,*,† Florence Lebon,§,† Franc¸ ois Durant,† Claude Giessner-Prettre,‡ Antonio Marquez,| and Nohad Gresh⊥ Faculte´ s UniVersitaires Notre-Dame de la Paix, Laboratoire de Chimie Mole´ culaire Structurale, 61 rue de Bruxelles, 5000 Namur, Belgium, Laboratoire de Chimie The´ orique, UMR7615, UniVersite´ Pierre & Marie Curie, 4, place Jussieu, 75252 Paris, France, Departamento de Qimica Fisica, Facultad de Qimica, UniVersitad de SeVilla, E-41012 SeVilla, Spain, and Laboratoire de Pharmacochimie Mole´ culaire et Structurale, FRE 2463 CNRS, U266 INSERM, UniVersite´ Rene Descartes, 4, aVenue de l’ObserVatoire, 75006 Paris, France ReceiVed: May 26, 2003; In Final Form: August 1, 2003
We have previously developed a new family of organometallic complexes targeting the HIV-1 protease, an enzyme that is essential for viral maturation. Among these, two Cu2+ complexes C1 and C2 were synthesized from flexible ligands L1, N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide and L2, N2-(2-methoxybenzyl)2-quinolinecarboxamide, respectively. These ligands, designed to fit the protease active site, were shown to form 2:1 complexes with Cu2+. To compare the relative stability of C1 and C2 and to study the energetic and structural aspects of such large Cu2+ complexes, we have extended the polarizable molecular mechanics procedure SIBFA to treat this cation. This was done by carrying out parallel ab initio (HF, MP2) as well as DFT computations. A first validation step was done on monoligated complexes, in which the SIBFA energy components were shown to correctly match their ab initio counterparts from an energy-decomposition procedure. Subsequent tests on polyligated Cu2+ complexes with neutral and anionic ligands showed the procedure to reproduce the results from MP2 and DFT computations with good accuracy (relative error
