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 con- verging rearrangements cannot be addressed by QM/MM MD due to the short time scale accessible. Extensive clas- sical 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 clas- sical 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 cispla- tin. 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.

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

RUGGERONE, PAOLO;
2008

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 con- verging rearrangements cannot be addressed by QM/MM MD due to the short time scale accessible. Extensive clas- sical 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 clas- sical 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 cispla- tin. 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.
Anticancer drugs; Drug-DNA interactions; Computer simulations
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/22160
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