Lessons learnt from assembling screening libraries for drug discovery for neglected diseases

TY - JOUR

T1 - Lessons learnt from assembling screening libraries for drug discovery for neglected diseases

AU - Brenk, Ruth

AU - Schipani, Alessandro

AU - James, Daniel

AU - Krasowski, Agata

AU - Gilbert, Ian Hugh

AU - Frearson, Julie

AU - Wyatt, Paul Graham

PY - 2008/3

Y1 - 2008/3

N2 - To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 252 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1697 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.

AB - To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 252 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1697 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.

KW - Compound selection

KW - High-throughput screening (HTS)

KW - Kinase inhibitors

KW - Neglected diseases

KW - Virtual screening

KW - HTS

U2 - 10.1002/cmdc.200700139

DO - 10.1002/cmdc.200700139

M3 - Article

SN - 1860-7187

VL - 3

SP - 435

EP - 444

JO - ChemMedChem

JF - ChemMedChem

IS - 3

ER -