Related Experiment Video
Updated: Jul 25, 2025
05:55
Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
6.8K
Identification of Potent hDHODH Inhibitors for Lung Cancer via Virtual Screening of a Rationally Designed Small
Hossam Nada1, Sungdo Kim1, Suin Park1
1BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
ACS Omega
|June 26, 2023
Summary
Researchers identified a novel compound, 5c, as a potent inhibitor of dihydroorotate dehydrogenase (DHODH) for lung cancer therapy. Compound 5c shows promising cytotoxicity and nanomolar inhibitory activity, outperforming a standard drug in early tests.
Area of Science:
- Biochemistry and Molecular Biology
- Medicinal Chemistry
- Computational Drug Discovery
Background:
- Cancer involves altered cellular metabolism, with metabolic enzymes as potential therapeutic targets.
- Pyrimidine metabolism is dysregulated in many cancers, especially lung cancer, a leading cause of mortality.
- Dihydroorotate dehydrogenase (DHODH), crucial for pyrimidine synthesis, is overexpressed in various cancers, including lung cancer.
Purpose of the Study:
- To discover novel dihydroorotate dehydrogenase (DHODH) inhibitors for lung cancer treatment.
- To identify potent anticancer compounds through rational drug design and computational methods.
Main Methods:
- Generation of a small combinatorial library followed by synthesis of top-hit compounds.
- In vitro anticancer activity testing against three lung cancer cell lines.
- In silico studies including DFT, molecular docking, molecular dynamics, and free energy calculations.
Main Results:
- Compound 5c exhibited significant cytotoxicity against the A549 lung cancer cell line (TC50 of 11 μM), surpassing the efficacy of Regorafenib (TC50 of 13 μM).
- Compound 5c demonstrated potent inhibition of human DHODH (hDHODH) with an IC50 value of 421 nM.
- Computational analyses elucidated key inhibitory mechanisms and structural features of the synthesized DHODH inhibitors.
Conclusions:
- Compound 5c represents a promising novel DHODH inhibitor for lung cancer therapy.
- The identified structural features and mechanisms are valuable for future drug development targeting DHODH.
