Off-Rate Screening (ORS) By Surface Plasmon Resonance. An Efficient Method to Kinetically Sample Hit to Lead Chemical Space from Unpurified Reaction Products

摘要

The dissociation rate constant k_d (off-rate) is the component of ligand?protein binding with the most significant potential to enhance compound potency. Here we provide theoretical and empirical data to show that this parameter can be determined accurately from unpurified reaction products containing designed test compounds. This screening protocol is amenable to parallel chemistry, provides efficiencies of time and materials, and complements existing methodologies for the hitto-lead phase in fragment-based drug discovery.