Identification of potential inhibitors of haloalkane dehalogenases by virtual screening

L. Daniel¹, J. Damborský^1,2, and J. Brezovský¹

¹Loschmidt Laboratories, Department of Experimental Biology and Research Centre for Toxic Compounds in the Environment, Faculty of Science, Masaryk University, Kamenice 5/A13, 625 00 Brno, Czech Republic;
²International Clinical Research Center, St. Anne's University Hospital Brno, Pekarska 53,
656 91 Brno, Czech Republic

lukecz.uo@gmail.com

Haloalkane dehalogenases (EC 3.8.1.5) are microbial enzymes which belong structurally to the α/β hydrolase fold. They are able to degrade a broad range of halogenated aliphatic hydrocarbons. However, their biological function still remains unknown with the exception of some particular strains [1,2].
An effective inhibitor of these enzymes may help to decipher their function. In this project, we applied AutoDockVina [3] docking software to screen the library of more than 140,000 compounds of the clean drug-like subset downloaded from the ZINC database [4]. For the detailed analysis, 10,000 molecules with the lowest docked energies were selected, and their docked conformations were rescored by a neural network-based scoring function NNScore 2.0 [5]. Additionally, their binding free energy was estimated using Molecular-Mechanics/Generalized-Born Surface Area (MM/GBSA). A consensus score for each docked ligand was then calculated by averaging the ranks obtained from MM/GBSA and NNScore 2.0 score. To increase the diversity of potential inhibitors, software AuposSOM [7] was employed to cluster the inhibitors accordingly to their common interactions with the enzyme. Finally, 100 top-ranked molecules were selected for experimental validation of their inhibitory activity.

This work was financially supported by the European Regional Development Fund (CZ.1.05/2.1.00/01.0001 and CZ.1.05/1.1.00/02.0123), by the Czech Grant Agency (203/08/0114 and P503/12/0572) and the Grant Agency of the Czech Academy of Sciences (IAA401630901). The access to computing facilities owned by parties and projects contributing to the MetaCentrum and listed at http://www.metacentrum.cz/acknowledgment/ is highly appreciated.