Discovery of Novel Haloalkane Dehalogenase Inhibitors

Authors

Buryska, T. , Daniel, L., Kunka, A., Brezovsky, J., Damborsky, J., Prokop, Z.

Source

APPLIED AND ENVIRONMENTAL MICROBIOLOGY 82: 1958-1965 (2016)

Abstract

Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step towards a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes’ known substrates and led to the discovery of less potent non-specific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of a HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 μM and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization.

Full text

Citation

Buryska, T. , Daniel, L., Kunka, A., Brezovsky, J., Damborsky, J., Prokop, Z., 2016: Discovery of Novel Haloalkane Dehalogenase Inhibitors. Applied and Environmental Microbiology 82: 1958-1965.

ELIXIR CZ annual conference 15 – 16 Nov, 2017
New video explaining the goals of Rafts4Biotech EU project
Invitation to a presentation by Synthetic Genomics
Andrea Schenkmayerova received a grant to attend an EMBO Practical Course
Open Postdoc Position: Protein Engineering
FireProt in MUNI
Jan Stourac won Dean’s Award