Introduction to Fragment-based Drug Discovery - Fragment-Based Drug Discovery - page 1

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Introduction to Fragment-based
Drug Discovery

Mike Cherry and Tim Mitchell

1.1 Introduction

Fragment screening is the process of identifying relatively simple, often weakly potent,
bioactive molecules. It is gaining wide acceptance as a successful hit-finding technique both
in its own right and as a method of finding hit molecules when traditional high-throughput
screening (HTS) methods fail. Fragment hits are typically highly 'ligand efficient', i.e. pos-
sess a high binding affinity per heavy atom, and thus are ideal for optimisation into clinical
candidates with good drug-like properties. Fragment screening is being increasingly proven
as a successful means of generating novel chemical starting material for drug discovery
programme s . It has been the subject of numerous publications and reviews in the last
few years. [ 1 5 ]
Fragment screening was initially developed to generate hit compounds against targets
for which other methods, such as HTS, had been unsuccessful. [ 6 ] At the same time, many
shortcomings of HTS were becoming increasingly apparent:

1. The hits being generated from high-throughput screening of combinatorial chemistry-
derived libraries are not particularly suitable for lead optimisation programmes: These
compounds tended to be large and hydrophobic and thus had limited potential for devel-
opment before becoming in violation of 'drug-like' parameters as described by Lipinski
et al . [ 7 ] 'Garbage in, garbage out really applies to drug screening', as Lipinski et al .
quote. [ 8 ]