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

• Published in: Journal of biomolecular NMR Vol. 31; no. 3; pp. 243 - 258
• Main Authors: Mercier, Kelly A, Powers, Robert
• Format: Journal Article
• Language: English
• Published: Netherlands Springer Nature B.V 01.03.2005
• Subjects: Chemistry, Pharmaceutical - methods; Cold Temperature; Drug Design; Drug Stability; Hydrogen-Ion Concentration; Instrumentation; Magnetic Resonance Spectroscopy - methods; Models, Chemical; NMR; Nuclear magnetic resonance; Pharmaceutical industry; Pharmaceutical Preparations - chemistry; Predictive Value of Tests; Protons; Solubility; Structure-Activity Relationship
• ISSN: 0925-2738; 1573-5001
• DOI: 10.1007/s10858-005-0948-4

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.