Publication details

Fast Screening of Inhibitor Binding/Unbinding using Novel Software Tool CaverDock

Authors

RANGEL PAMPLONA PIZARRO PINTO José Gaspar VÁVRA Ondřej FILIPOVIČ Jiří ŠTOURAČ Jan BEDNÁŘ David DAMBORSKÝ Jiří

Year of publication 2019
Type Article in Periodical
Magazine / Source FRONTIERS IN CHEMISTRY
MU Faculty or unit

Faculty of Science

Citation
Web Full Text
Doi http://dx.doi.org/10.3389/fchem.2019.00709
Keywords binding; docking; channel; unbinding; virtual screening; inhibitors; substrates; tunnel
Description Protein tunnels and channels are attractive targets for drug design. Drug molecules that block the access of substrates or release of products can be efficient modulators of biological activity. Here, we demonstrate the applicability of a newly developed software tool CaverDock for screening databases of drugs against pharmacologically relevant targets. First, we evaluated the effect of rigid and flexible side chains on sets of substrates and inhibitors of seven different proteins. In order to assess the accuracy of our software, we compared the results obtained from CaverDock calculation with experimental data previously collected with heat shock protein 90 alpha. Finally, we tested the virtual screening capabilities of CaverDock with a set of oncological and anti-inflammatory FDA-approved drugs with two molecular targets-cytochrome P450 17A1 and leukotriene A4 hydrolase/aminopeptidase. Calculation of rigid trajectories using four processors took on average 53 min per molecule with 90% successfully calculated cases. The screening identified functional tunnels based on the profile of potential energies of binding and unbinding trajectories. We concluded that CaverDock is a sufficiently fast, robust, and accurate tool for screening binding/unbinding processes of pharmacologically important targets with buried functional sites. The standalone version of CaverDock is available freely at https://loschmidt.chemi.muni.cz/caverdock/and the web version at https://loschmidt.chemi.muni.cz/caverweb/.
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