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A QM/MM Investigation of the Antitumor Drug Neocarzinostatin

Under the influence of heat or light, enediynes convert to para‐benzenes via the Bergman cyclization reaction. The resulting para‐benzyne moiety can abstract hydrogen atoms from DNA leading to DNA unraveling and subsequent cell death. Neocarzinostatin is a natural product drug molecule that contains an enediyne. In order to evaluate the effectiveness of neocarzinostatin as a cancer drug, we utilized computational chemistry to evaluate the mechanism whereby neocarzinostatin undergoes the Bergman cyclization and abstracts H atoms in the presence of DNA. We used docking methods available in GLIDE to generate initial poses which were subsequently subjected to long time scale molecular dynamics to explore the conformational flexibility and binding affinity of the DNA:neocarzinostatin complex. We then used the QM/MM (Quantum Mechanics/Molecular Mechanics) ONIOM method to study the barriers for neocarzinostatin Bergman cyclization in the presence of DNA as well as the mechanism for H abstraction. This study will allow us to investigate both the interaction of a cancer drug with DNA as well as the energy necessary to influence the Bergman cyclization reaction.