Bifunctional Binding of Cisplatin to DNA:  Why Does Cisplatin Form 1,2-Intrastrand Cross-Links with AG But Not with GA?

Abstract

The bifunctional binding of the anticancer drug cisplatin to two adjacent nucleobases in DNA is modeled using density functional theory. Previous experimental studies revealed that cisplatin binding to adjacent guanine and adenine is sensitive to nucleobase sequence. Whereas AG 1,2-intrastrand cross-links are commonly observed, the analogous GA adducts are not known. This study focuses on understanding this directional preference by constructing a full reaction profile using quantum chemical simulation methods. Monofunctional and bifunctional cisplatin adducts were generated, and the transition states that connect them were located for the dinucleotides d(pApG) and d(pGpA), assuming that initial platination takes place at the guanine site. Our computer simulations reveal a significant kinetic preference for formation of the AG over the GA adduct. The activation free energies of approximately 23 kcal/mol for AG and approximately 32 kcal/mol for GA suggest that bifunctional closure is approximately 6 orders of magnitude faster for AG than for GA. A strong hydrogen bond between one of the ammine ligands of cisplatin and the 5' phosphate group of the DNA backbone is responsible for the stabilization of the transition state that affords the AG adduct. This interaction is absent in the transition state that leads to the GA adduct because the right-handed helix of the DNA backbone places the phosphate out of reach for the ammine ligand. We found only an insignificant thermodynamic difference between AG and GA adducts and conclude that the preference of AG over GA binding is largely under kinetic control. The puckering of the deoxyribose ring plays an important role in determining the energetics of the bifunctional platination products. Whereas the 3'-nucleoside remains in the native C2'-endo/C3'-exo form of B-DNA, the deoxyribose of the 5'-nucleoside always adopts the C2'-exo/C3'-endo puckering in our simulations. A detailed analysis of the energies and structures of the bifunctional adducts revealed that the observed sugar puckering patterns are necessary for platinum to bind in a relaxed coordination geometry.

Combined Theoretical and Computational Study of Interstrand DNA Guanine–Guanine Cross-Linking by trans-[Pt(pyridine)2] Derived from the Photoactivated Prodrug trans,trans,trans-[Pt(N3)2(OH)2(pyridine)2]

“…[3][4][5] Extensive research has been reported which elucidates cisplatin's mechanism of action. 2,[6][7][8][9][10] Upon administration, the relatively high concentration of chloride ions in blood (~100 mM) maintains cisplatin in a neutral state. Inside the cell, the lower chloride ion concentrations (~4-20 mM) facilitate activation of cisplatin by stepwise aquation, and subsequent reaction with various cellular targets, most notably DNA.…”

A DFT study of a novel oxime anticancer trans platinum complex: Monofunctional and bifunctional binding to purine bases

“…In recent years, theoretical and computational methods have increasingly supported the search for new platinum drugs. Cisplatin has been intensively studied at theoretical level from various aspects, including its structure [31], the hydrolysis process [32][33][34][35], interaction with DNA [36][37][38][39][40][41], the hydrogenbonding influence on the Pt-DNA adducts [42], and other aspects [43,44]. To clarify the preference of cisplatin for guanine over adenine, Baik et al [45] carried out DFT studies on the first substitution of cisplatin binding to purine bases.…”

Ethaselen: a novel organoselenium anticancer agent targeting thioredoxin reductase 1 reverses cisplatin resistance in drug-resistant K562 cells by inducing apoptosis

“…Cisplatin exerts its anticancer activity by forming 1,2-intrastrand cisplatin-DNA cross-links (Mantri et al, 2007;Yaneva et al, 2007;Harrington et al, 2010). However, a serious limitation in cancer chemotherapy with cisplatin is the development of drug resistance.…”