Role of 6-Mercaptopurine in the potential therapeutic targets DNA base pairs and G-quadruplex DNA: insights from quantum chemical and molecular dynamics simulations

Abstract

The theoretical studies on DNA with the anticancer drug 6-Mercaptopurine (6-MP) are investigated using theoretical methods to shed light on drug designing. Among the DNA base pairs considered, 6-MP is stacked with GC with the highest interaction energy of –46.19 kcal/mol. Structural parameters revealed that structure of the DNA base pairs is deviated from the planarity of the equilibrium position due to the formation of hydrogen bonds and stacking interactions with 6-MP. These deviations are verified through the systematic comparison between X–H bond contraction and elongation and the associated blue shift and red shift values by both NBO analysis and vibrational analysis. Bent’s rule is verified for the C–H bond contraction in the 6-MP interacted base pairs. The AIM results disclose that the higher values of electron density (ρ) and Laplacian of electron density (∇²ρ) indicate the increased overlap between the orbitals that represent the strong interaction and positive values of the total electron density show the closed-shell interaction. The relative sensitivity of the chemical shift values for the DNA base pairs with 6-MP is investigated to confirm the hydrogen bond strength. Molecular dynamics simulation studies of G-quadruplex DNA d(TGGGGT)₄ with 6-MP revealed that the incorporation of 6-MP appears to cause local distortions and destabilize the G-quadruplex DNA.

Keywords:

• DNA
• 6-Mercaptopurine
• cancer
• quantum chemical calculations
• molecular dynamics simulation

Acknowledgment

We are thankful to DST-SERB-Fast Track Project grant No: SR/FTP/PS-151/2011 & 22.05.2012 for financial assistance. We are extremely grateful to Dr. L. Sandhiya (Ludwig Maximilian University, Munich) and Dr. Lourdes del Olmo (Universidad Autónoma de Madrid, Spain) for their kind support. We are also thankful to CMSD (Center for Modelling Simulation and Design) Center of DST Government of India at Hyderabad for providing computational facilities.