| The protein tubulin is an essential structural protein required for life and reproduction of all eukaryotic cells. Its function involves dynamic interplay between polymerized and depolymerized states. Drugs that change the dynamic behavior of tubulin, such as the compound Taxol, have been found to be clinically useful for treatment of diseases involving misregulated cell growth, such as cancer. We have used computational modeling and simulation coupled with data from crystallographic analysis of protein/drug complexes to define the bound conformation of two compounds that bind to the same site and stabilize tubulin polymers, Taxol and EpothiloneA. Further, we have used computational simulation to explain activities of these drugs in cells due to changes in the chemical character of the binding site. Importantly, we show that the differing resistance profiles for these two classes of compounds result from fundamentally different patterns of interaction with the protein receptor. We also present models for the interaction of two additional drugs with different tubulin sites, colchicine and laulimalide, that explain much of their observed pharmacology. The use of computational models as tools for understanding molecular pharmacology and development of new drugs with enhanced properties is discussed. |
