Determining the optimal size of small molecule mixtures for high throughput NMR screening

Authors

Kelly A. Mercier, University of Nebraska - Lincoln
Robert Powers, University of Nebraska - LincolnFollow

Date of this Version

March 2005

Comments

Published in Journal of Biomolecular NMR 31 (2005), pp. 243–258. Copyright © 2005 Springer. Used by permission. DOI 10.1007/s10858-005-0948-4 http://www.springerlink.com/content/1573-5001/

Abstract

High-throughput screening (HTS) using NMR spectroscopy has become a common component of the drug discovery effort and is widely used throughout the pharmaceutical industry. NMR provides additional information about the nature of small molecule-protein interactions compared to traditional HTS methods. In order to achieve comparable efficiency, small molecules are often screened as mixtures in NMR-based assays. Nevertheless, an analysis of the efficiency of mixtures and a corresponding determination of the optimum mixture size (OMS) that minimizes the amount of material and instrumentation time required for an NMR screen has been lacking. A model for calculating OMS based on the application of the hypergeometric distribution function to determine the probability of a 'hit' for various mixture sizes and hit rates is presented. An alternative method for the deconvolution of large screening mixtures is also discussed. These methods have been applied in a high-throughput NMR screening assay using a small, directed library.