Computational insight to structural aspects of Crispine-DNA binding

Crispines are naturally occurring isoquinoline alkaloids with potent cytotoxic activity reported against SKOV3, KB and Hela human cancer cell lines. The structural details on the drug-receptor interactions that induce cytotoxic activity are important factors to be considered in drug development and repurposing studies. In the present study, cytotoxic mechanism of Crispine variants; Crispine A and Crispine B with double-stranded DNA has been investigated through computational techniques including molecular docking, molecular dynamics simulations, and quantum mechanical calculations. Analysis of the drug binding mode, conformational perturbations induced by the binding of the drug, receptor and ligand flexibility in dynamic solvent environment and energetics of the complex formation clearly suggests that Crispine B portrays partial intercalation stabilized by hydrophobic interactions and binds to DNA with better affinity than Crispine A, the latter prefers the minor groove even in the presence of an intercalation cavity in DNA. The presence of the pi-electrons system in Crispine B enhances the molecular planarity and aromaticity to provide enough stacking forces and supports partial intercalation. Both the variants show minimal changes in terms of structure but induce significant change in DNA conformation to support cytotoxic behavior.