Theoretic study of DNA base guanine and adenine and protein residues’ binding mode of the trans geometries of new antitumor non-classical platinum complexes containing pyridine and picoline ligand

Abstract

The first and second substitution reactions of five activated trans platinum (II) compounds with DNA purine bases and protein residues are explored here. The free energy barriers relative to the first substitutions of these compounds are 19.5/22.9 kcal/mol (trans-[PtCl2(NH3)pyridine], (1), 16.5/14.6 kcal/mol (trans-[PtCl2(pyridine)2], (2), 18.3/18.0 kcal/mol (trans-[PtCl2(NH3)(2-picoline)], (3), 16.4/18.4 kcal/mol(trans-[PtCl2(NH3)(3-picoline)], (4), and 17.5/18.7 kcal/mol (trans-[PtCl2(NH3)(4-picoline)], (5), starting from trans-Pt-chloroaqua to trans-Pt-G/A monoadduct, while 22.5/24.8 kcal/mol(1), 18.5/23.9 kcal/mol(2), 24.3/24.9 kcal/mol(3), 23.3/24.3 kcal/mol(4), and 18.7/24.0 kcal/mol(5) are observed for trans-Pt-diaqua → trans-Pt-G/A monoadduct. In the second substitutions, reaction barriers for (G-Pt-G) head-to-head (HH)/head-to-tail (HT) formation are 17.6/16.3 kcal/mol(1), 17.7/14.8 kcal/mol(2),17.7/17.3 kcal/mol(3),18.9/18.0 kcal/mol(4), and 22.4/21.7 kcal/mol(5). Corresponding values for (G-Pt-A) HH/HT formation are 20.8/20.8(1), 24.9/22.9(2), 27.3/21.6(3), 27.5/24.6(4), and 28.1/25.4(5) kcal/mol in turns. The competition reactions reveal that for 1 and 4, methionine residue stabilizes the transition state (ΔGaq/ZPE = 13.1/12.7 kcal/mol) for platination more efficiently than purine bases and other protein residues, while cysteine residue owns the lower barrier height (11.1/13.4/11.8 kcal/mol) for 2, 3, and 5. The binding mechanism of trans platinum complexes containing planar amines, trans-[PtCl2(L)(L′)] (where L = L′ = pyridine; L = NH3, L′ = pyridine, or L′ = 2-picoline, 3-picoline, 4-picoline), with DNA and protein residues has been theoretically investigated. Our calculations reveal that the symmetric compound trans-[PtCl2(pyridine)2] is the most kinetically and thermodynamically preferred one not only for binding with guanine in the first substitution but also for binding with cysteine in the second substitution.