Parameterization of azole‐bridged dinuclear platinum anticancer drugs via a QM/MM force matching procedure

Abstract

Azole-bridged diplatinum compounds are promising new anticancer drugs designed to induce small distortions upon DNA alkylation, able to circumvent resistance problems of existing platinum drugs. Hybrid quantum classical (QM/MM) molecular dynamics (MD) simulations of different azole-bridged platinum drugs have recently revealed the nature of the local deformations at the DNA binding site. However, the description of global slow converging rearrangements cannot be addressed by QM/MM MD due to the short time scale accessible. Extensive classical MD simulations are therefore mandatory to describe accurately the structural distortions in the DNA double helix. This issue is now addressed by developing a new set of accurate force field parameters of the platinated moiety via a recently proposed force matching procedure of the classical forces to ab initio forces obtained from QM/MM trajectories. The accuracy of our force field parameters is validated by comparison of structural properties from classical MD and hybrid QM/MM simulations. The structural characteristics of the Pt-lesion are well reproduced during classical MD compared with QM/MM simulations and available experimental data. The global distortions in the DNA duplex upon binding of dinuclear Pt-compounds are very small and rather opposite to those induced by cisplatin. Thus, the force match approach significantly extends the potentialities of molecular simulations in the study of anticancer drugs and of the interactions with their biological targets.

Developing accurate molecular mechanics force fields for conjugated molecular systems

“…In an attempt to parameterize bimolecular FFs using the FM method, Maurer et al employed a quantum mechanics/molecular mechanics (QM/MM) approach to derive FFs that reproduce the steric, electrostatic, and dynamic properties of the QM subsystem. 50 Works along this line were also carried out to produce FFs for azole-bridged dinuclear platinum anticancer drugs 51 , zinc in metalloproteins 41 , and the 11-cis protonated schiff base chromophore of Rhodopsin. 52 Recently, the method has also been extended to 4 parameterized FFs along a reaction path.…”

Quantum Mechanical Methods for Drug Design

“…QM is being used routinely in optimizing geometries, fitting the torsion parameters, and deriving atomic charges for proteins [97], DNA [98], and in particular small molecules [99][100][101][102]. Spiegel and coworkers developed a new set of FF parameters of platinated moiety via a force matching procedure of the classical forces to ab initio forces obtained from QM/MM trajectories, and extended the classical MD simulation to describe slow converging rearrangement of dinuclear Pt compounds and DNA duplex [103]. Sugiyama and coworkers used DFT calculated partial charges and FF parameters for the atoms near the active site, which are usually significantly polarized, and metal atoms for which FF parameters are not available [104].…”

Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid Ab initio Quantum Mechanics/Molecular Mechanics

“…A recent review reports CPMD/MM applications that address this issue. 169 The method has also recently provided valuable insights on DNA damage 16,[170][171][172][173][174][175] and on the binding of anticancer drugs to DNA [176][177][178][179][180] or to the copper transport protein, [181][182][183] which is supposed to function as a transporter of cisplatin.…”