Modeling of Copper(II) Complexes with the SIBFA Polarizable Molecular Mechanics Procedure. Application to a New Class of HIV-1 Protease Inhibitors

Abstract

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 Cu 2+ 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 Cu 2+ . To compare the relative stability of C1 and C2 and to study the energetic and structural aspects of such large Cu 2+ 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 Cu 2+ complexes with neutral and anionic ligands showed the procedure to reproduce the results from MP2 and DFT computations with good accuracy (relative error <3%). We have next extended the calculations to compare the C1 and C2 complexes. Energy balances including continuum solvation effects indicate a greater stability of the C1 complex, in agreement with experimental results. The effects of the methoxyphenyl substituents on the C1 complex stability were further investigated and compared to their concomitant influences on the ab initio-computed molecular electrostatic potential.

Protein Tyrosine Phosphatase Inhibition by Metals and Metal Complexes

“…Some investigations have indicated that proteasome inhibition is involved in the apoptosis of cancer cells induced by copper complexes (15,16,18,104). Copper complexes have been designed as human immunodeficiency virus type 1 (HIV-1) protease inhibitors (56,57). Thus, cellular proteins are possible targets of therapeutic copper complexes.…”

Structure Prediction of Bis(amino acidato)copper(II) Complexes with a New Force Field for Molecular Modeling

“…50 A ReaxFF reactive force field, in which the parameters were fitted to a substantial database of quantum chemical data (binding energies, ground-state systems, full reactive pathways), was developed for reactions involving carbon materials and transition metal atoms, including copper, usually employed in catalytic transformations. 51 The force field was applied for high-temperature MD simulations in the presence of metal atoms and carbon fragments, which demonstrated different catalytic abilities of the metals in the formation of small polycyclic structures serving as nucleation points for further nanostructure formation.…”

Inclusion of the ligand field contribution in a polarizable molecular mechanics: SIBFA‐LF

“…We used the AOM formalism to derive an explicit energy contribution that was integrated in the SIBFA procedure along with its five Δ E int components. Such an integration was done with only minor recalibrations of the sole Cu(II) parameters that were originally derived for the E rep , E ct , and E disp contributions in the absence of ligand field effects 16. It is noted that, except for the newly introduced formamidate nitrogen, all non‐Cu(II) parameters were kept unchanged.…”

“…Because some of us became recently interested in the extension of polarizable molecular mechanics to complexes containing Cu(II) cation,16 we found necessary to refine its representation by SIBFA because this systematic, in its actual formulation, was not able to give the Jahn–Teller geometric characteristics exhibited by systems such as Cu(II)‐(H 2 O) 6 or Cu(II)‐(NH 3 ) 4 . Because of the importance of the ligand–ligand interactions in the overall complex energetics it is desirable to have a systematic able to give both correct ligand–ligand and metal–ligand distances.…”