Computer modeling, synthesis and biological evaluation of selective inhibitors of Golgi mannosidase II
APVV project 0117-06 (February 2007 - December 2009)

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The project deals with a design of new anticancer agents based on the selective inhibition of human Golgi alpha-mannosidase II with minimal side effects toward human alpha-lysosomal mannosidase. Based on crystalographic and biochemical data 3D structures of human Golgi and lysosomal alpha-mannosidases will be prepared using homology modeling. New compounds derived from swainsonine- and mannostatin-type inhibitors will be designed for the human Golgi mannosidase II with the aid of virtual screening, docking, 3-D pharmacophore modeling and molecular dynamic simulations. Selective structures will be synthesized and test their biological activity in vitro against recombinant Golgi and lysosomal alpha-mannosidases.

Swainsonine- and mannostatin-type inhibitors

We assume to develop a novel selective inhibitor - structural analogue of swainsonine and mannostatin (an inhibitor with Ki/IC50 ratio hLM/hGM > 10). Main effort will be focused on the improvement of the selectivity of inhibitors toward human Golgi alpha-mannosidase II maintaining their potency at the level of swainsonine and mannostatin. The other goal of the project is to characterize structures of transition states of the catalytic mechanism of retaining alpha-mannosidases II by means of the quantum mechanics and hybrid QM/MM methods.