Computational Analysis and Experimental Testing of the Molecular Mode of Action of Gatastatin and Its Derivatives

SIMPLE SUMMARY: The glaziovianin A derivative gatastatin, presented as a γ-tubulin-specific inhibitor, could represent a viable chemotherapeutic strategy to solve the specificity issues associated with targeting α and β tubulin. Since gatastatin’s specificity for γ tubulin has not been confirmed by an in silico analysis or verified experimentally by other groups, we undertook finding a molecular-level elucidation of the binding mode of gatastatin and comparing its predicted binding affinity values for both α-β and γ tubulin. We believe that our paper opens the possibility for the rational design of a long-sought candidate drug with desired specificity and selectivity for γ tubulin. ABSTRACT: Given its critical role in cell mitosis, the tubulin γ chain represents a viable chemotherapeutic target to solve the specificity issues associated with targeting α and β tubulin. Since γ tubulin is overexpressed in glioblastoma multiforme (GBM) and some breast lesions, the glaziovianin A derivative gatastatin, presented as a γ-tubulin-specific inhibitor, could yield a successful therapeutic strategy. The present work aims to identify the binding sites and modes of gatastatin and its derivatives through molecular-docking simulations. Computational binding free energy predictions were compared to experimental microscale thermophoresis assay results. The computational simulations did not reveal a strong preference toward γ tubulin, suggesting that further derivatization may be needed to increase its specificity.