Exploring Purine Analogues as Inhibitors against Katanin, a Microtubule Severing Enzyme using Molecular Modeling Approach

Katanin, a pioneering microtubule-severing enzyme, is a novel AAA-ATPase protein. It severs microtubules by forming hexamers that binds to the C-terminal tails of tubulin, using ATP hydrolysis to generate the force necessary to break the microtubule lattice. Katanin contributes to microtubule amplification and impact the growth of carcinomas. Hence, katanin is a highly promising target for anti-cancer drug development. This study aims to identify potential purine-based inhibitors against katanin by using structure-based virtual screening, PASS and ADME-T prediction, docking, and molecular dynamics simulations. Here, purine-based library of 2,76,280 compounds from the PubChem Database were utilized, and top two purine type inhibitors (PubChem ID: 122589735, and 123629569) were selected based on superior binding energy, ADME-T, and biological activity. Furthermore, molecular docking and molecular dynamics simulations study revealed that 122589735 and 123629569 compounds effectively alter katanin's structure and dynamics as compared to ATP. Besides, binding energy calculations indicate that 122589735 exhibits higher binding affinity with katanin compared to 123629569 and ATP. Thus, our computational study identifies potential purine-based katanin inhibitors that exhibit higher affinity for katanin than ATP and may have implications for various carcinomas. This research paves the way for developing novel, anti-cancer therapies targeting a range of carcinoma types.