Molecular dynamic simulations of the intercalation of benzothiopyranoindazole anticancer analogs with DNA models

Fixed valence geometry intermolecular energy scans were carried out for a series of eight substituted anti-cancer benzothiopyranoindazoles (BTPI) interacting with (G-C) duplex models for DNA. The apparent intercalation energy minima identified in these scans were subsequently used as starting points in full-cartesian molecular dynamics relaxation simulations for 14 BTPIs. Intercalation in the major groove is preferred when both the ligand and DNA model possess formal charges. Otherwise, insertion of the ligand is modestly preferred from the minor groove. There are multiple minimum energy intercalation complexes within 5 kcal/mol of a global minimum for most analogs studied. The intercalation complex was investigated as a function of the molecular dielectric constant, epsilon, and the length of the (G-C) duplex segment. A wide range of epsilon values (3.5-50) can be employed without changing the relative order of stability of intercalation complexes. However, the absolute intercalation energy is quite sensitive to the selection of epsilon. (G-C)6 duplexes appear to be of adequate length to determine reliable estimates of the relative intercalation energetics.