Title:Identification of a Chemical Inhibitor with a Novel Scaffold Targeting
Decaprenylphosphoryl-β-D-Ribose Oxidase (DprE1)
Volume: 23
Issue: 5
Author(s): Tatsuki Matsunaga, Kohei Monobe and Shunsuke Aoki*
Affiliation:
- Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu
Institute of Technology, Iizuka, Japan
Keywords:
Dpre1, tuberculosis, inhibitors, virtual screening, molecular docking, molecular dynamics.
Abstract:
Background: Tuberculosis is the second leading cause of death from infectious diseases
worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating
a crisis. Hence, there is a need to develop anti-tuberculosis drugs with novel structures and versatile
mechanisms of action.
Objective: In this study, we identified antimicrobial compounds with a novel skeleton that inhibits
mycobacterium decaprenylphosphoryl-β-D-ribose oxidase (DprE1).
Methods: A multi-step, in silico, structure-based drug screening identified potential DprE1 inhibitors
from a library of 154,118 compounds. We experimentally verified the growth inhibitory effects of the
eight selected candidate compounds against Mycobacterium smegmatis. Molecular dynamics simulations
were performed to understand the mechanism of molecular interactions between DprE1 and ompound
4.
Results: Eight compounds were selected through in silico screening. Compound 4 showed strong
growth inhibition against M. smegmatis. Molecular dynamics simulation (50 ns) predicted direct and
stable binding of Compound 4 to the active site of DprE1.
Conclusion: The structural analysis of the novel scaffold in Compound 4 can pave way for antituberculosis
drug development and discovery.