Screening of Enzyme Activators

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The modulation of enzyme activity is critical in both drug discovery and enzyme product development. While inhibitors are extensively studied, enzyme activators—molecules that enhance enzymatic activity—are often overlooked despite their importance in regulating enzyme function and improving process efficiency. Creative Enzymes provides specialized services to identify, evaluate, and characterize enzyme activators. Leveraging advanced assay platforms, high-throughput screening, and a decade of enzymology expertise, we deliver precise and reproducible data to support enzyme optimization, therapeutic research, and biotechnological applications.

What Are Enzyme Activators and How to Screen Activators

Activators play a pivotal role in situations where upregulation of enzyme activity is essential. In drug development, certain drug candidates require enhanced enzymatic activity for efficacy. In industrial enzyme production, activators can be employed to boost activity under specific conditions, improving yield and functionality.

Enzyme activators for glucose-6-phosphate dehydrogenase and sirtuin 1 Figure 1. Examples of enzyme activators. The production of glucose-6-phosphate from glucose is accelerated by RO281675 and compound A, while Sirt1 production of deacylated products from acetyl-lysine residues is promoted by Resveratrol and SRT1720. (Kenakin, 2017)

Identifying suitable activators is inherently more challenging than identifying inhibitors for several reasons:

Assay Requirements: Enhanced enzyme activity can reduce assay time but necessitates larger quantities of substrate.
Mechanistic Diversity: Activators may function through allosteric regulation, substrate interactions, or other indirect mechanisms, often without strong binding affinity to the enzyme.
Structural Variability: Unlike inhibitors, which often resemble enzyme substrates, activators can be chemically diverse, making initial screening strategies less straightforward.

These challenges demand specialized methodologies. Creative Enzymes has developed robust, sensitive assays and high-throughput platforms specifically designed for activator identification, ensuring reliable and actionable results.

Our Comprehensive Solutions to Identify Enzyme Activators

Our Screening of Enzyme Activators service provides comprehensive solutions to identify molecules that enhance enzymatic activity.

Service	Details
Quantitative Evaluation of Activators	Accurate measurement of enzymatic enhancement under various conditions.
Batch-Based Assessment	Comparative analysis of multiple activator candidates in parallel.
High-Throughput Screening (HTS)	Evaluation of pre-built libraries containing over 10,000 candidate compounds to discover potent activators.
Assay Versatility	Both surface-based and solution-based assay formats are available.
Enzyme Profiling	Assess activator effects in different biological contexts, including disease states, or under treatment with drugs, growth factors, or hormones.
Customized Consultative Support	Feasibility assessments and guidance from experienced enzymologists to optimize assay design and activator discovery.

Our goal is to provide precise, reliable, and reproducible data to enable clients to harness enzyme activators for research, therapeutic development, and industrial applications.

Our Screening Strategies and Methodologies

Strategy 1 for enzyme activators screening

Biochemical Activity-Based High-Throughput Screening (HTS)

Our primary approach for activator discovery measures the direct increase in catalytic activity upon compound addition. This method enables rapid evaluation of large chemical libraries to identify molecules that enhance reaction rates.

Strategy 2 for enzyme activators screening

Binding Assays

These assays detect compounds that interact with the enzyme's active or allosteric sites. Binding is often a critical first step toward activation and provides valuable insights into potential mechanisms, even before functional effects are confirmed.

Strategy 3 for enzyme activators screening

Fragment-Based Screening (FBS)

FBS allows the identification of small molecular fragments that bind to novel or allosteric regions of the enzyme. These fragments can serve as starting points for developing potent activators with precise mechanistic control.

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Enzyme Activators Screening Services Workflow

Workflow of Creative Enzymes' enzyme activator screening services

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Our Advantages

Specialized Expertise

Decade-long experience in enzyme assay development and activator identification.

High-Throughput Capabilities

Screen libraries exceeding 10,000 compounds efficiently.

Versatile Assay Platforms

Support both solution-phase and surface-phase assays.

Mechanistic Insight

Identify not just potent activators but also their modes of action.

Quantitative & Comparative Analysis

Reliable, batch-based evaluation of multiple candidates simultaneously.

Consultative Collaboration

Tailored guidance to optimize screening strategies and experimental design.

Case Studies and Real-World Applications

Case 1: Discovery of LYPLAL1 Enzyme Activators Using ABPP

Activity-based protein profiling (ABPP), traditionally used to discover enzyme inhibitors, has been adapted to identify small-molecule enzyme activators. Using a fluorescence polarization–ABPP assay, researchers uncovered compounds that enhance the activity of LYPLAL1, a serine hydrolase linked to metabolic regulation. Through ABPP-guided medicinal chemistry, a selective LYPLAL1 activator suitable for in vivo use was developed. Structural and biochemical analyses revealed that activation occurs by improving the efficiency of the catalytic triad. In a mouse model of diet-induced obesity, treatment with the activator improved metabolic outcomes, demonstrating ABPP's potential to uncover enzyme activators across diverse enzyme families.

Graphical abstract illustrating discovery of small-molecule enzyme activators using activity-based protein profiling (ABPP) Figure 2. Graphic abstract showing workflow of discovery of small-molecule enzyme activators by activity-based protein profiling. (Kok et al., 2020)

Case 2: Allosteric Modulators for Insulin-Degrading Enzyme (IDE)

The insulin-degrading enzyme (IDE) is a zinc-dependent peptidase involved in breaking down insulin and amyloidogenic peptides like β-amyloid, linking it to both diabetes and Alzheimer's disease. However, IDE's precise role remains unclear due to its atypical clamshell structure and recently discovered non-proteolytic functions. These diverse activities complicate therapeutic strategies, as IDE can act on multiple substrates and influence cellular systems beyond proteolysis. Both activation and inhibition of IDE have been explored as treatments for T2DM and AD, but inconsistent data and potential off-target effects pose challenges. Deeper insight into IDE's structure–function relationships and non-catalytic roles is crucial for developing safe, effective therapies.

Mechanism of insulin-degrading enzyme (IDE) activators Figure 3. Experimentally determined structure of the human dimeric IDE in a complex with BDM41367 (PDB ID:4DTT). (Tundo et al., 2023)

FAQs About Our Enzyme Activators Screening Services

Q: What types of enzymes can be screened for activators?

A: We support a wide variety, including oxidoreductases, hydrolases, transferases, and synthetases. Both soluble and membrane-associated enzymes can be evaluated.
Q: Can I provide my own candidate library for screening?

A: Yes. Clients may supply custom libraries, or we can utilize our in-house curated collections, which contain thousands of diverse molecules optimized for activator discovery.
Q: Can high-throughput screening (HTS) be applied to my enzyme?

A: Absolutely. We have HTS capabilities for libraries containing over 10,000 compounds, combining automated platforms with sensitive detection systems to rapidly identify potential activators.
Q: What types of assays are available for activator screening?

A: Both solution-based and surface-based assays are available, selected based on the enzyme type, activator mechanism, and project objectives. This ensures robust and reproducible detection of activity enhancement.
Q: How do you handle activators that work through unconventional mechanisms?

A: Our assays are designed to detect a wide range of mechanisms, including allosteric regulation, substrate interaction enhancement, and structural stabilization, not just strong binding interactions.
Q: Can this service help optimize enzymes for industrial or therapeutic applications?

A: Yes. The identified activators can be directly applied to improve catalytic efficiency, stability, or activity in both research and industrial processes, supporting enzyme product development and therapeutic enzyme studies.
Q: What data and reporting will I receive after the screening?
A: You will receive a comprehensive report including:
- Raw assay data and statistical analysis
- Quantitative comparison of activator potency
- Mechanistic insights, such as allosteric or substrate-mediated effects
- Recommendations for further development or optimization
Q: How long does a typical activator screening project take?

A: Depending on enzyme complexity and library size, projects typically require 4–8 weeks from assay development to final reporting.

References:

Kenakin TP. Enzymes as drug targets. In: Pharmacology in Drug Discovery and Development. Elsevier; 2017:131-156. doi:10.1016/B978-0-12-803752-2.00006-5
Kok BP, Ghimire S, Kim W, et al. Discovery of small-molecule enzyme activators by activity-based protein profiling. Nat Chem Biol. 2020;16(9):997-1005. doi:10.1038/s41589-020-0555-4
Tundo GR, Grasso G, Persico M, et al. The insulin-degrading enzyme from structure to allosteric modulation: new perspectives for drug design. Biomolecules. 2023;13(10):1492. doi:10.3390/biom13101492

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