Methods for kinetic evaluation of reversible covalent inhibitors from time-dependent IC50 data

Lavleen K Mader1, Jeffrey W Keillor1

  • 1Department of Chemistry and Biomolecular Sciences, University of Ottawa Ottawa Ontario K1N 6N5 Canada jkeillor@uottawa.ca.

PubMed
Summary

New methods quantify time-dependent inhibition kinetics for reversible covalent drugs. These tools help accurately rank drug candidates by analyzing incubation time-dependent IC50 data for better drug development.

Related Concept Videos

Introduction to Enzyme Kinetics01:19

Introduction to Enzyme Kinetics

Enzyme kinetics studies the rates of biochemical reactions. Scientists monitor the reaction rates for a particular enzymatic reaction at various substrate concentrations. Additional trials with inhibitors or other molecules that affect the reaction rate may also be performed.
The experimenter can then plot the initial reaction rate or velocity (Vo) of a given trial against the substrate concentration ([S]) to obtain a graph of the reaction properties. For many enzymatic reactions involving a...
19.5K
Enzyme Kinetics01:19

Enzyme Kinetics

Enzymes speed up reactions by lowering the activation energy of the reactants. The speed at which the enzyme turns reactants into products is called the rate of reaction. Several factors impact the rate of reaction, including the number of available reactants. Enzyme kinetics is the study of how an enzyme changes the rate of a reaction.
Scientists typically study enzyme kinetics with a fixed amount of enzyme in the controlled environment of a test tube. When more reactant, or substrate, is...
95.3K
Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
77.5K
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
12.7K
Determination of Michaelis Constant and Maximum Elimination Rate01:20

Determination of Michaelis Constant and Maximum Elimination Rate

The Michaelis constant (KM) and the theoretical maximum process rate (Vmax) are vital parameters in the Michaelis-Menten equation, central to many biochemical reactions. They provide essential insights into enzyme kinetics and drug metabolism.
These parameters can be estimated by analyzing plasma concentration data post-drug administration. A notable example of this application is phenytoin, a drug with capacity-limited kinetics. It's recommended that phenytoin should be administered at two...
52
Measuring Reaction Rates03:09

Measuring Reaction Rates

Polarimetry finds application in chemical kinetics to measure the concentration and reaction kinetics of optically active substances during a chemical reaction. Optically active substances have the capability of rotating the plane of polarization of linearly polarized light passing through them—a feature called optical rotation. Optical activity is attributed to the molecular structure of substances. Normal monochromatic light is unpolarized and possesses oscillations of the electrical...
24.2K