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Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine
Published on: February 16, 2018
The rational discovery of multipurpose inhibitors of the ornithine decarboxylase
Xiaoying Chai1,2,3, Jingqiong Zhan2,4, Jing Pan1,2
1National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China.
Abstract:
Metabolic reprograming is a hallmark of cancer, and the polyamine metabolic network is dysregulated in many cancers. Ornithine decarboxylase (ODC) is a rate-limiting enzyme for polyamine synthesis in the polyamine metabolic network. In many cancer cells, ODC is over-expressed, so this enzyme has been an attracting anti-cancer drug target. In the catalysis axis (pathway), ODC converts ornithine to putrescine. Meanwhile, ODC's activity is regulated by protein-protein interactions (PPIs), including the ODC-OAZ1-AZIN1 PPI axis and its monomer-dimer equilibrium. Previous studies showed that when ODC's activity is inhibited, the PPIs might counteract the inhibition efficiency. Therefore, we proposed that multipurpose inhibitors that can simultaneously inhibit ODC's activity and perturb the PPIs would be very valuable as drug candidates and molecular tools. To discover multipurpose ODC inhibitors, we established a computational pipeline by combining positive screening and negative screening. We used this pipeline for the forward screening of multipurpose ligands that might inhibit ODC's activity, block ODC-OAZ1 interaction and enhance ODC non-functional dimerization. With a combination of different experimental assays, we identified three multipurpose ODC inhibitors. At last, we showed that one of these inhibitors is a promising drug candidate. This work demonstrated that our computational pipeline is useful for discovering multipurpose ODC inhibitors, and multipurpose inhibitors would be very valuable. Similar with ODC, there are a lot of proteins in human proteome that act as both enzymes and PPI components. Therefore, this work is not only presenting new molecular tools for polyamine study, but also providing potential insights and protocols for discovering multipurpose inhibitors to target more important protein targets.
Insights
Researchers developed a computational method to find dual-action drugs targeting cancer-related Ornithine Decarboxylase (ODC). This approach identified promising multipurpose inhibitors that block enzyme activity and disrupt protein interactions, offering new cancer treatment strategies.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Metabolic reprogramming, including polyamine pathway dysregulation, is a key feature of cancer.
- Ornithine decarboxylase (ODC), a rate-limiting enzyme in polyamine synthesis, is over-expressed in many cancers and is a significant drug target.
- ODC activity is modulated by protein-protein interactions (PPIs), which can counteract direct enzyme inhibition.
Purpose of the Study:
- To develop multipurpose inhibitors that simultaneously inhibit ODC enzyme activity and disrupt its critical PPIs.
- To establish a computational pipeline for identifying such dual-action inhibitors.
- To evaluate the potential of these inhibitors as anti-cancer drug candidates and molecular tools.
Main Methods:
- Development of a computational pipeline integrating positive and negative screening strategies.
- Forward screening of ligands designed to inhibit ODC activity, block ODC-OAZ1 interaction, and promote ODC non-functional dimerization.
- Validation of identified compounds using a combination of experimental assays.
Main Results:
- Identification of three multipurpose ODC inhibitors through the computational pipeline and experimental validation.
- One identified inhibitor demonstrated significant promise as a drug candidate.
- The study validated the utility of the computational pipeline for discovering multipurpose inhibitors.
Conclusions:
- Multipurpose inhibitors targeting both ODC activity and PPIs are valuable for cancer therapy and polyamine research.
- The developed computational pipeline is effective for discovering such inhibitors.
- This approach provides a framework for developing multipurpose inhibitors against other dual-function protein targets in the human proteome.
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