Coupling CP-MD Simulations and X-ray Absorption Spectroscopy: Exploring the Structure of Oxaliplatin in Aqueous Solution

Abstract

A combined experimental-theoretical approach applying X-ray absorption spectroscopy and ab initio molecular dynamics (CP-MD) simulations is used to get insight into the structural determination of oxaliplatin, a third-generation anticancer drug of the cisplatin family, in aqueous solution. Experimental Pt L(III)-edge EXAFS and XANES spectra of oxaliplatin in water are compared with theoretical XAS spectra. The latter are obtained as statistically averaged spectra computed for a set of selected snapshots extracted from the MD trajectory of ethyldiamineoxalatoplatinum(II) (EDO-Pt) in liquid water. This compound is a simplified structure of oxaliplatin, where the outer part of the cyclohexane ring contained in the cyclohexanediamine ligand of oxaliplatin has been removed. We show that EDO-Pt is an appropriate model to simulate the spectroscopical properties of oxaliplatin given that the cyclohexane ring does not generate particular features in neither the EXAFS nor the XANES spectra. The computation of average EXAFS spectra using structures from the MD simulation in which atoms are selected according to different cutoff radii around the Pt center allows the assignment of spectral features to particular structural motifs, both in k and R-spaces. The outer oxygen atoms of the oxalate ligand (R(Pt-O(II)) = 3.97 +/- 0.03 A) are responsible for a well-defined hump at around 6.5 A(-1) in the k(2)-weighted EXAFS spectrum. The conventional EXAFS analysis data procedure is reexamined by its application to the simulated average EXAFS spectra. The structural parameters resulting from the fit may then be compared with those obtained from the simulation, providing an estimation of the methodological error associated with the global fitting procedure. A thorough discussion on the synergy between the experimental and theoretical XAS approaches is presented, and evidence for the detection of a slight hydration structure around the Pt complex is shown, leading to the suggestion of a new challenge to experimental XAS measurements.

EXAFS Debye-Waller factors issued from Car-Parrinello molecular dynamics: Application to the fit of oxaliplatin and derivatives

“…The remaining scattering paths have low contributions to the EXAFS signal. In our previous study, 21 we have shown that the solvation structure could hardly be detected, only on the simulated spectrum, at a distance of 4.14 Å from platinum. The solvent contribution is too low to be detected on our experimental structures.…”

“…9,10,22,24 In this work, the solvation structure has not been included, neither in the computation of simulated spectra nor in the fitting procedure, because its contribution is really small to the EXAFS function. (CP-MD simulations show that the first shell of water molecules is at a 4.14 Å distance from platinum 20,21 ; refer also to Sec. II C).…”

“…In this work, we extend our first study 21 to the extraction of information on DWs from the CP-MD trajectory and their use in new approaches for accurate constrained EXAFS fitting. For both single scattering and multiple scattering paths, analysis of the distance distributions is used to support the DWs estimation on the basis of the second cumulant, as proposed by Merkling et al 10 Then they are used either through their absolute values coming from the simulation or some of their ratios.…”

“…17 The comparison of theoretical XANES and EXAFS spectra calculated either using a unique structure of oxaliplatin or EDO-Pt, or averaging on a significant number of structures extracted from the EDO-Pt trajectory, showed that EDO-Pt is a good spectroscopical model for oxaliplatin. 21 The systematic errors, associated with the distances determination in a standard EXAFS fitting approach, were assessed by fitting both the simulated and experimental spectra under the same conditions.…”

Synchrotron Radiation Spectroscopic Techniques as Tools for the Medicinal Chemist: Microprobe X-Ray Fluorescence Imaging, X-Ray Absorption Spectroscopy, and Infrared Microspectroscopy

“…Some of the most prominent studies include those associated with the anti-cancer drug, cisplatin. Solutions of the platinum-containing drug, cisplatin, [71] and its derivative, oxaliplatin, [72] have been analysed by bulk XAS to confirm the presence of axial water ligands. Bulk XAS has also been used for the development of controlled release drug delivery systems by confirming the integrity of drugs in the delivery agent; a specific example being the use of XAS to confirm that the structure of cisplatin did not alter following its incorporation into poly(ethylene oxide) gel.…”