Kutchukian, Peter, Lindvall, Mika, Wright, Kirk, Ottl, Johannes, Jacob, Jaison, Scheufler, Clemens, Marzinzik, Andreas, Natasja, Brooijmans and Glick, Meir (2013) Beyond Consensus: Leveraging Inherent Biases in Fragment Based Screening Technologies. Journal of medicinal chemistry.

Abstract

Fragment-based drug discovery (FBDD) has emerged as a strategy with great potential to recast the modern drug discovery process. Central to this method is the identification of small and simple molecular building blocks that bind a target of interest, and the subsequent incorporation of salient features of these fragments into larger and more complex compounds with enhanced target affinity and selectivity. A first step in FBDD often entails a fragment-based screen (FBS) to identify fragment “hits.” While there are theoretical advantages of using FBDD at the earliest stages of a drug discovery program, hurdles such as the integration of conflicting results from orthogonal screens have hindered its success. We present the meta-analysis of 35 fragment based campaigns at Novartis, which employed a generic 1,400 fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we aim to answer three questions: 1) What makes a fragment amenable for FBS? 2) How do different fragment screening technologies compare with each other? 3) What is the best way to pair FBS assay technologies? In addition to identifying properties that render fragments amenable for FBS, we compare in an unprecedented scale various screening technologies. We propose a quantitative way to compare the bias in various screening technologies, and demonstrate how this approach can be used to select technologies in order to ensure the greatest coverage of fragment hits.

Item Type:	Article
Date Deposited:	27 May 2016 23:45
Last Modified:	06 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/10998