Identification of potential inhibitors of haloalkane dehalogenases by virtual screening


L. Daniel1, J. Damborský1,2, 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


Haloalkane dehalogenases (EC 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  is highly appreciated.