Computational study on mechanisms of the anticancer drug: Cisplatin and novel polynuclear platinum(II) interaction with sulfur-donor biomolecules and DNA purine bases

•Understand cisplatin and novel polynuclear platinum(II) interaction with biological targets.•Compare calculation results with B3LYP and M06 functional methods.•Compare computational result for diaqua-cisplatin reaction with purine bases obtained by Raber et al.

In this paper, we explore the monofunctional substitution reactions between cisplatin and novel polynuclear platinum(II) (BBR3005 and BBR3464) hydrolyzed complexes and sulfur-donor biomolecules (glutathione, methionine and cysteine) and purine bases (guanine and adenine) in DNA with two different DFT-B3LYP/M06 functional methods and IEF-PCM solvation model. The computed activation energy barrier of chloroaqua-Pt (BBR3464) and diaqua-Pt (BBR3464) complexes binding to guanine (G), adenine (A), and glutathione (GSH) in the aqueous solution with B3LYP functional method is 17.9/17.9 kcal/mol, 19.9/19.8 kcal/mol, and 13.2/14.6 kcal/mol, respectively. What is more, the computed activation energy barrier for substitution reaction of diaqua-cisplatin with DNA by B3LYP functional method is 20.1 kcal/mol (11.2 kcal/mol for M06 functional method) for guanine (G) (experimental value = 18.3 kcal/mol) and 22.3 kcal/mol (15.5 kcal/mol for M06 functional method) for adenine (A), which shows that the B3LYP functional method may be more suitable for platinum-DNA system calculation compared with M06 functional method. Our calculation demonstrates that GSH is more favorable intracellular targets than Met, Cys and DNA purine bases for BBR3464, which is also consistent with the results that platinum(II) has high affinity for binding to S-donors biomolecules especially glutathione compared with N-donors biomolecules such as DNA purine bases.The calculated activation energies barrier of interaction of polynuclear platinum(II) with purine bases are lower than those of cisplatin no matter we use B3LYP or M06 functional method, which confirms that anticancer activity of polynuclear platinum(II) is higher than cisplatin as suggested by experiment.

Graphical abstractIn this study, the monofunctional substitution reactions of hydrated forms of cisplatin and novel polynuclear platinum(II) (BBR3005 and BBR3464) with sulfur-donor biomolecules (glutathione, methionine and cysteine) and DNA purine bases is followed by using two different B3LYP and M06 hybrid functional method.Whole reaction process is described as the following figure:Download high-res image (95KB)Download full-size image