The influence of lead discovery strategies on the properties of drug candidates
Top Cited Papers
- 1 March 2009
- journal article
- research article
- Published by Springer Nature in Nature Reviews Drug Discovery
- Vol. 8 (3) , 203-212
- https://doi.org/10.1038/nrd2796
Abstract
Despite the widespread acceptance of guidelines related to desirable physicochemical properties of potential small-molecule drugs, key properties — such as lipophilicity — of recently developed clinical candidates and advanced lead compounds have been shown to differ significantly from those of historical leads and drugs. By analysing the physicochemical properties of a large database of hits and corresponding leads identified in the past decade, we show that this undesirable phenomenon can be traced back to the nature of high-throughput screening hits and hit-to-lead optimization practices. Conceptual and organizational adjustments may be required to enable a smooth lead-evolution process that reduces the chance of high compound-related attrition in clinical trials.Keywords
This publication has 43 references indexed in Scilit:
- Recent Developments in Fragment-Based Drug DiscoveryJournal of Medicinal Chemistry, 2008
- The influence of drug-like concepts on decision-making in medicinal chemistryNature Reviews Drug Discovery, 2007
- Lead-like, drug-like or “Pub-like”: how different are they?Journal of Computer-Aided Molecular Design, 2007
- Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical librariesProceedings of the National Academy of Sciences, 2006
- Improving success rates for lead generation using affinity binding technologiesCurrent Opinion in Biotechnology, 2005
- How can we avoid the productivity gap?Drug Discovery Today, 2005
- High-Throughput Screening: Searching for Higher ProductivitySLAS Discovery, 2004
- Ligand efficiency: a useful metric for lead selectionDrug Discovery Today, 2004
- A ‘Rule of Three’ for fragment-based lead discovery?Drug Discovery Today, 2003
- Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug DiscoveryJournal of Chemical Information and Computer Sciences, 2001