A new class of drug compounds, designed to disarm a key defense mechanism of tuberculosis, has been proposed by a joint research team from Japan and Thailand.
Toyohashi, Japan & Ubon Ratchathani, Thailand – A research collaboration between Toyohashi University of Technology (Japan) and Ubon Ratchathani University (Thailand) has proposed novel compounds as potential therapeutic agents for tuberculosis. The compounds are designed to inhibit the drug-metabolizing enzyme cytochrome P450 (CYP), which is released by Mycobacterium tuberculosis.
Background and Mechanism
Rifampicin, a commonly used tuberculosis drug, induces the activity of CYP. This induction accelerates the metabolism of co-administered drugs, reducing their efficacy. The proposed compounds aim to inhibit CYP activity, preventing the degradation of these co-administered drugs. Because the agents target an enzyme released by the bacterium rather than the bacterium itself, the likelihood of resistance development may be reduced.
Methodology and Findings
Previous studies identified the heme group as CYP's active site and established that coordination bonds between heme iron and inhibitors are necessary for inhibition. Standard molecular simulations could not accurately reproduce this coordination bond.
"Accurately describing the binding state around heme iron was a major challenge." — Graduate students Masato Nagura and Misaki Chimura
The research team constructed a new molecular force field that incorporates coordination bonding and charge transfer around the heme iron. This new method successfully reproduced the experimentally observed structure of a CYP-inhibitor complex. Using the fragment molecular orbital (FMO) method, researchers identified amino acid residues critical for inhibitor binding.
Based on an existing inhibitor (15b), the team introduced substituents at a specific position to design 11 novel compounds. Molecular simulations indicated that two of these compounds exhibited stronger binding to CYP than existing inhibitors, suggesting they may be effective CYP inhibitors. The compounds were selected based on favorable drug properties and low predicted toxicity.
Development Process
The lead authors of the two research papers, graduate students Masato Nagura and Misaki Chimura, noted that accurately describing the binding state around heme iron was a major challenge. Collaboration with researchers in Thailand enabled more efficient searching for compounds. Nagura and Chimura spent two months at the Thailand laboratory.
Future Plans
The novel molecular simulation method will be applied to other enzyme proteins to identify new inhibitory compounds. Synthesized compounds will be evaluated in cell-based experiments at the Thailand laboratory. Associate Professor Kurita and graduate students plan to visit Thailand to develop a detailed implementation plan. Collaborative research and student exchanges between the two universities have been ongoing for over 10 years.
Publications
The research was reported in two papers:
- Y. Nagura et al. (2024) J. Mol. Graph. Model., 133, 108875.
- N. Chimura et al. (2026) In Silico Research in Biomedicine, 2, 100373.
Funding and Acknowledgments
This research was supported by the Japan Student Services Organization (JASSO) International Internship Program and the student exchange program between Toyohashi University of Technology and Ubon Ratchathani University. Supercomputing resources were provided by the supercomputer Fugaku at RIKEN, Japan (Project Number: hp250154).