CD BioSciences is committed to developing and applying a variety of advanced biophysical techniques to drug-target binding kinetic measurements. We provide our customers with detailed kinetic data in a structural context to facilitate medicinal chemistry approaches to kinetic optimization within the constraints of the relevant pharmacokinetic parameters.

Background

Binding kinetics is of increasing interest to the drug discovery community. It has been reported that predicting the efficacy of new drugs in vivo and in humans by measuring unbinding kinetics can guide leads optimization to improve efficacy and safety. The process of drug binding to its target is considered to be a multi-step response mechanism. The final on and off rates may be influenced by microscopic rate constants related to binding and unbinding, target protein conformational changes and/or isomerization, and so on.

The time of contact between a drug and its target (often referred to as residence time) is now considered a key parameter for optimization, which can predict drug efficacy in vivo and may even be more effective than traditional thermodynamic parameters (free energy, entropy, enthalpy). Many of the available biophysical methods can be used to predict the residence time of drug targets and provide kinetic data during the lead optimization phase of drug discovery. These data can be applied to the rational modulation of kinetics.

Fig.1 Schematic representation of protein-ligand binding mechanisms and associated kinetic constants. (Bernetti, 2019)

Our Techniques for Measuring Binding Kinetics

• Label-based (radioligand-based and fluorescence-based) methods.

• Scintillation proximity analysis (SPA)
• Fluorescence polarisation (FP)
• Förster resonance energy transfer (FRET)
• Fluorescence intensity (FLINT)

• Label-free methods.

• SPR-based biosensors
• Biolayer interferometry
• DNA nanometre levers
• Resonant waveguide grating
• Liquid chromatography electrospray ionization tandem mass spectrometry (LC‐ESI‐MS/MS)

Our Services

We offer multiple biophysical methods to help our customers measure ligand binding kinetics, as well as explore the effect of molecular level factors on binding kinetics and the role that residence times have on pharmacokinetics, pharmacodynamics, and efficacy. The services we offer include, but are not limited to:

• Measurement of ligand binding kinetics.

• Characterization of the association rate constant/on-rate (K_on).
• Characterization of the dissociation rate constant/off-rate (K_off).

• Measurement of structure–kinetic relationships.
• Evaluation of enzyme inhibitors in drug discovery.
• Establishment of the drug-target residence time models.

Applications

• Research on effects of conformational dynamics on binding kinetics. 
• Research on mechanism of binding and kinetics.
• Optimizing residence time.
• Research on effects of pharmacokinetics and pharmacodynamics.

CD BioSciences has developed a number of experimental and modeling methods for studying pharmacokinetics to provide accurate and detailed ligand binding kinetic parameters for our clients. We look forward to working with you and helping you make better predictions to improve the efficacy and safety of your drugs. If you are interested in our services, please contact us for more details.

Reference

1. Bernetti, M.; et al. Kinetics of drug binding and residence time. Annual review of physical chemistry. 2019, 70: 143-171.

• Drug Design Based on X-ray Crystallography
• Thermodynamic Characterization of Biomolecular Interactions
• Target Binding Analysis by HDX-MS
• Binding Affinity Measurement by MST
• Protein Stability Evaluation by TSA
• Fragment Screening Based on WAC
• Hit Identification by NMR-based Techniques
• Qualification of Targeting Protein-Protein Interactions
• Identification of Small-Molecule Aggregation
• Analysis of Free Energy Calculations
• Modeling of Scaffold Hopping Transformations
• Cellular Imaging Service for Drug Discovery
• AFM-Based Biophysical Analysis of Drugs