Molecular modeling study of binding between DNA and CC-1065 analogue

COMP 191

Guangyu Sun, Laboratory of Medicinal Chemistry, CCR, NCI-Frederick, NIH, 376 Boyles St., Frederick, MD 21702, Marc C Nicklaus, mn1@helix.nih.gov, Laboratory of Medicinal Chemistry, CCR, NCI, NIH, Bidg.376 Boyles Street, Frederick, MD 21702, Denise P. Simmons, Laboratory of Cellular Carcinogenesis and Tumor Promotion/CCR/NCI/NIH, 37 Convent Dr, Bethesda, MD 20892, and Jing-Yu Lai, CovX, 9381 Judicial Dr, San Diego, CA 92121.
A newly designed CC-1065 analogue, which is based on methyl carbamate and aimed at eliminating the irreversible hepatic and renal toxicities of CC-1065 while retaining its antitumor activity that many existing analogues lack, has shown high reactivity toward DNA segments 5'-AATTA* and 5'-AGTTA* but low reactivity toward 5'-AAAAA* in in vitro evaluation. In order to explain its different alkylation reactivities toward different DNA segments, long molecular dynamics (MD) simulations (generally >1ns) have been performed with AMBER program, using both implicit and explicit solvation models. In both types of simulations, the bound complexes remained stable throughout the simulation. The binding energy, calculated as the difference in potential energy between the complex and free DNA and ligand, shows that the binding between the ligand with 5'-AATTA* and 5'-AGTTA* is stronger than with 5'-AAAAA*. These data support our hypothesis that the CC-1065 analogue will form stable DNA complexes. The data also correlate well with our experimental observations that this analogue has a sequence preference for 5'-AATTA*, 5'-AGTTA*, followed by 5'-AAAAA*, supporting the notion that pre-alkylation binding dominates the analogue's reactivity with different DNA sequences. Among the different energy components, contributions from the van der Waals and 1-4 electrostatic energy terms account for most of the differences in the total binding energies among various DNA segments. Similar results were obtained from MD simulations using explicit water solvent.