Structure-based rationalization of antitumor drugs mechanism of action by a MIF approach

Structural patterns for antitumor drugs, evidenced by means of a molecular interaction field (MIF) approach using grid independent descriptors (GRIND), resembled closely those of a previous independent pharmacological classification based on their antitumor mechanism of action. For topoisomerase II inhibitors, antimitotic agents and DNA antimetabolites, systematic structural patterns were evidenced by MIF and the structural features of "outliers" in these classes corresponded to peculiar pharmacological mechanisms of action supported by literature evidences. Alkylating agents and DNA/RNA antimetabolites, interacting with a large variety of targets by different molecular mechanisms, did not exhibit clustering in the structure-based MIF approach. Moreover MIFS were able to point out similarities between drugs which, in spite of apparent dramatic differences in chemical structure, exhibit the same pharmacological behaviour.