Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases

Ruth Brenk,Daniel James,Agata Krasowski,Ian Hugh Gilbert,Alessandro Schipani,Julie Frearson,Paul Graham Wyatt

doi:10.1002/cmdc.200700139

Abstract

To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 552 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1 697 compounds for a focused kinase set. Compiling these libraries required a robust strategy for compound selection. Rules for unwanted groups were defined and selection criteria to enrich for lead-like compounds which facilitate straightforward structure–activity relationship exploration were established. Further, a literature and patent review was undertaken to extract key recognition elements of kinase inhibitors (“core fragments”) to assemble a focused library for hit discovery for kinases. Computational and experimental characterisation of the general screening library revealed that the selected compounds 1) span a broad range of lead-like space, 2) show a high degree of structural integrity and purity, and 3) demonstrate appropriate solubility for the purposes of biochemical screening. The implications of this study for compound selection, especially in an academic environment with limited resources, are considered.

Highlights

The pharmaceutical industry has a long track record of delivering innovative therapeutics
To select a library of a size that is suitable for an environment with restricted resources, such as hit discovery for orphan or neglected diseases, we established a series of selection filters to identify a lead-like library of compounds which would be regarded by medicinal chemists as good starting points for optimisation campaigns
Purity, and solubility assessments and diversity analysis showed that the general screening library is of high quality

Summary

Introduction

The pharmaceutical industry has a long track record of delivering innovative therapeutics. To tackle orphan or neglected diseases either the pharmaceutical industry must be given incentives to work on them or not-for-profit organisations need to be enabled to do drug discovery.[3,5] Increasingly, academic groups are either partnering with industry or are recruiting experienced people from industry to guide and support their drug discovery efforts, creating an environment which allows professional translational research and opens up access to key technologies, such as screening facilities and libraries for hit discovery.[6]

Methods

Results

Discussion

Conclusion