Entropy and Enthalpy in the Activity of Tubulin-Based Antimitotic Agents

Microtubules are important biological targets of antitumor chemotherapy. Tubulin polymerization inhibitors (TPIs) hinder polymerization whereas microtubule stabilizing agents (MSAs) promote tubulin polymerization and stabilize microtubules. The goal of enhancing binding affinity through favorable (positive) entropic contributions, a significant part of medicinal chemistry dogma, hinges on a rather simplistic assumption that ligand-protein binding interactions are primarily entropically driven. In turn, individual contributions of enthalpy and entropy to the overall potency of small molecules rarely are determined. Herein, we describe various antimitotic agents whose interactions with tubulin were explored and in which the individual enthalpic and entropic contributions were evaluated. These examples clearly demonstrate that the binding affinities of small molecules with their target proteins are more complex than often articulated; one should exercise caution when rationalizing the relative activity of these molecules and their analogues.