Intercalation Ability of Novel Monofunctional Platinum Anticancer Drugs: A Key Step in Their Biological Action
Daniele Veclani, Marilena Tolazzi, José P. Cerón‐Carrasco, Andrea Melchior
Abstract
quantum mechanical (QM) methods, hybrid QM/QM' schemes, and independent gradient model approaches are implemented in an unbiased protocol. The performed simulations show that the cascade of reactions is articulated in three well-defined stages: (i) an early and fast intercalation of the complex between the DNA bases, (ii) a subsequent hydrolysis reaction that leads to the aqua-activated form, and (iii) a final formation of the covalent bond between PtPPH and DNA at a guanine site. The permanent damage to DNA is consequently driven by that latter bond to DNA but with a simultaneous π-π intercalation of the phenanthridine into nucleobases. The impact of the DNA sequence and the lateral backbone was also discussed to provide a more complete picture of the forces that anchor the drug into the double helix.