Ligand Design for E3 Ligase
We offer professional E3 ligase ligand design and optimization services, addressing key challenges in PROTAC development. These challenges include E3 ligase ligand selection, affinity enhancement, and specificity optimization. With advanced technology platforms and a professional research team, we are committed to providing efficient and reliable E3 ligase ligand solutions to help achieve breakthrough progress in PROTAC drug development.
What is E3 Ligase and E3 Ligase Ligand?
Ubiquitin (UB) is a protein modifier that regulates many important cellular processes. In order to initiate protein modification through UB, E1 enzyme activates the C-terminal carboxylate of UB to transfer to the target protein through E1-E2-E3 cascade. E3 is a ubiquitous protein ligase, which directly or indirectly catalyzes the transfer of ubiquitous proteins to target proteins (substrates) to form heteropeptide bonds. By using small molecular ligands to recruit target proteins and E3 ligand, all small molecular PROTAC has achieved rapid target degradation and better cell permeability. Various small molecules that have been shown to bind to several E3 ligase or substrate receptor proteins of the CRL E3 ligase complex, such as MDM2,cIAP1,CRBN and VHL, have been used in PROTAC development.
Challenges We Help Solve
Insufficient affinity of E3 ligase ligands: This leads to weak binding between PROTAC molecules and E3 ligases, impacting the degradation efficiency of target proteins.
Poor specificity of E3 ligase ligands: This can cause non-specific binding to other proteins, leading to side effects.
Lack of suitable ligands: For some novel or hard-to-target E3 ligases, it is difficult to find appropriate ligands.
Poor cell membrane permeability: Some ligands are unable to pass through the cell membrane, limiting the activity of PROTACs within cells.
Suboptimal pharmacokinetic properties: The metabolism stability and half-life of ligands in the body affect the efficacy and safety of PROTACs.
Detailed Ligand Design Services
Ligand Screening
High-throughput screening: Using advanced high-throughput screening equipment and a rich compound library, we quickly identify ligands with potential activity against the target E3 ligase.
Structure-based screening: Combining techniques like X-ray crystallography and cryo-EM, we analyze the complex structure of E3 ligases with ligands, providing a structural foundation for ligand screening.
Ligand Structure Optimization
Computational drug design: Using molecular docking and molecular dynamics simulations, we predict the binding mode and affinity of ligands with E3 ligases, guiding ligand design and optimization.
Medicinal chemistry modifications: We employ medicinal chemistry methods to modify ligand structures, enhancing their affinity, specificity, and pharmacokinetic properties.
Structure-based Design
Structural biology research: Using techniques like X-ray crystallography and cryo-EM, we determine the structure of E3 ligases to provide detailed structural information for ligand design.
Structural optimization: Based on structural data, we optimize the ligand design to improve binding efficiency with E3 ligases.
Biological Activity Evaluation
In vitro experiments: Using various in vitro models such as enzyme activity assays and cell proliferation inhibition experiments, we assess the impact of ligands on E3 ligase activity and the degradation efficiency of target proteins by PROTAC molecules.
Cell-based assays: Using cell models, we evaluate the membrane permeability, intracellular stability, and ability of ligands to promote target protein degradation.
Pharmacokinetic Research
In vivo metabolism studies: We study the absorption, distribution, metabolism, and excretion (ADME) processes of ligands in the body to evaluate their pharmacokinetic properties.
Metabolic stability optimization: Through structural optimization, we enhance the metabolic stability of ligands and extend their half-life in the body.
Workflow of Ligand Design Services
- Requirement Communication and Assessment: We engage in in-depth discussions with clients to understand project requirements, including details about target E3 ligases and target proteins, assess project feasibility, and develop a detailed research plan.
- Project Initiation: Based on the research plan, we form a professional team, allocate tasks, and begin ligand screening and design work.
- Ligand Design and Optimization: Using various technological approaches, we carry out ligand design and optimization, providing regular progress reports to clients.
- Biological Activity Evaluation: We assess the biological activity of optimized ligands, verifying their affinity and specificity for E3 ligases and their ability to promote PROTAC functionality.
- Pharmacokinetic Research: We conduct pharmacokinetic studies to evaluate the stability, half-life, and other parameters of ligands in vivo.
- Project Delivery and Ongoing Support: We provide clients with complete experimental data, research reports, and optimized ligands, along with ongoing technical support and consultation services.
Why Choose Our Services?
Professional R&D Team: Our team consists of experienced medicinal chemists, biologists, and computational chemists, equipped with deep theoretical knowledge and practical experience.
Advanced Technology Platforms: We are equipped with leading international computational chemistry and molecular simulation platforms, high-throughput screening platforms, biochemistry and cell biology platforms, and pharmacokinetic research platforms, providing robust technical support for E3 ligase ligand design and optimization.
Extensive Project Experience: We have rich experience in the PROTAC field, having successfully completed multiple E3 ligase ligand design and optimization projects, enabling us to quickly and accurately address challenges faced by clients during R&D.
Rigorous Quality Control: We have established a comprehensive quality control system, ensuring that every stage from raw material procurement to experimental operations and data analysis is strictly monitored, ensuring high-quality services and products.
Efficient Project Management: We use scientific project management methods to allocate resources and time effectively, ensuring that projects are delivered on time and helping clients accelerate their R&D progress.
Technology Platforms
Computational Chemistry and Molecular Simulation Platform: We use molecular docking, molecular dynamics simulations, and other computational methods to predict the binding mode and affinity of ligands with E3 ligases, guiding ligand design and optimization.
High-throughput Screening Platform: Equipped with advanced high-throughput screening equipment and a comprehensive compound library, we rapidly identify ligands with potential activity against target E3 ligases.
Biochemistry and Cell Biology Platform: We have well-established biochemistry and cell biology experimental conditions, allowing us to perform various in vitro and cell-based experiments to evaluate ligand biological activity and the degradation efficiency of target proteins by PROTAC molecules.
Pharmacokinetic Platform: Equipped with advanced analytical instruments, we conduct comprehensive studies on the pharmacokinetic properties of ligands, providing critical information for their drug-likeness evaluation.
Frequently Asked Questions (FAQs)
1. How do you ensure the E3 ligase ligands you design have high specificity and affinity?
We use multiple strategies to ensure ligand specificity and affinity. First, we employ advanced computational chemistry and molecular simulation techniques to predict and optimize the binding mode of ligands with E3 ligases. Second, we combine high-throughput screening and structural biology research to identify ligands with potential activity from a large compound pool, further optimizing their structures. Finally, we conduct rigorous biological activity assessments and pharmacokinetic studies to select ligands with high specificity and affinity.
2. What are the costs of your services?
Service prices vary based on project requirements, research content, and complexity. We develop personalized pricing plans based on the detailed information provided by the client. Additionally, we offer flexible cooperation models and favorable pricing policies to meet different client needs. If you're interested in our services, please feel free to contact us for detailed pricing information.
References:
- Buckley, D. L., Gustafson, J. L., Van Molle, I., Roth, A. G., Tae, H. S., Gareiss, P. C., ... & Crews, C. M. (2012). Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α. Angewandte Chemie International Edition, 51(46), 11463-11467.
- Steinebach, C., Kehm, H., Lindner, S., Vu, L. P., Köpff, S., Mármol, Á. L., ... & Gütschow, M. (2019). Protac-mediated crosstalk between E3 ligases. Chemical communications, 55(12), 1821-1824.
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
