Molecular modelling of a sequence-specific DNA-binding agent based on the pyrrolo[2, 1-c][1,4]benzodiazepines

The CHARMm force field was used for the first time to model the tricyclic pyrrolobenzodiazepine (PBD) ring system. This system forms the core of the well known sequence-selective DNA-interactive anthramycin-type antitumour antibiotics. The results agreed with previous results obtained using the AMBER and X-PLOR force fields. The simple family member DC-81 preferentially binds in the 5S orientation with S-stereochemistry at the C11 position of the PBD and with the A-ring of the molecule oriented towards the 5′ end of the covalently bound strand. The modelling studies and energetic analyses also support the observation that the molecules have a sequence preference for the purine-guanine-purine motif.