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 gamma-tubulin-specific inhibitor, could represent a viable chemotherapeutic strategy to solve the specificity issues associated with targeting alpha and beta tubulin. Since gatastatin's specificity for gamma 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 alpha-beta and gamma 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 gamma tubulin. Given its critical role in cell mitosis, the tubulin gamma chain represents a viable chemotherapeutic target to solve the specificity issues associated with targeting alpha and beta tubulin. Since gamma tubulin is overexpressed in glioblastoma multiforme (GBM) and some breast lesions, the glaziovianin A derivative gatastatin, presented as a gamma-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 gamma tubulin, suggesting that further derivatization may be needed to increase its specificity.

Automated summary

This study aims to identify the binding sites and modes of gatastatin and its derivatives through molecular docking simulations, and compare the computational binding free energy predictions with experimental results. The computational simulations did not show a strong preference for gamma tubulin, suggesting that further derivatization may be needed to increase its specificity.