Paper Info
Title
Current trends in lead discovery: Are we looking for the appropriate properties?
Abstract
Summary The new drug discovery paradigm is based on high-throughput technologies, both with respect to synthesis and screening. The progression HTS hits → lead series → candidate drug → marketed drug appears to indicate that the probability of reaching launched status is one in a million. This has shifted the focus from good quality candidate drugs to good quality leads. We examined the current trends in lead discovery by comparing MW (molecular weight), LogP (octanol/water partition coefficient, estimated by Kowwin (17)) and LogSw (intrinsic water solu- bility, estimated by Wskowwin (18)) for the following categories: 62 leads and 75 drugs (11); compounds in the development phase (I, II, III and launched), as indexed in MDDR; and compounds indexed in medicinal chemistry journals (ref. 20), categorized according to their biological activity. Comparing the distribution of the above prop- erties, the 62 lead structures show the lowest median with respect to MW (smaller) and LogP (less hydrophobic), and the highest median with respect to LogSw (more soluble). By contrast, over 50% of the medicinal chemistry compounds with activities above 1 nanomolar have MW > 425, LogP > 4.25 and LogSw < -4.75, indicating that the reported active compounds are larger, more hydrophobic and less soluble when compared to time-tested quality leads. In the MDDR set, a progressive constraint to reduce MW and LogP, and to increase LogSw, can be observed when examining trends in the developmental sequence: phase I, II, III and launched drugs. These trends indicate that other properties besides binding affinity, e.g., solubility and hydrophobicity, need to be considered when choosing the appropriate leads.
Year
DOI
Venue
2002
10.1023/A:1020877402759
Journal of computer-aided molecular design
Keywords
DocType
Volume
database filtering,drug-likeness,drug research,hydrophobicity,lead-likeness,property distribution,`rule of 5' test,solubility
Journal
16
Issue
ISSN
Citations 
5-6
0920-654X
16
PageRank 
References 
Authors
3.53
2
1
Name
Order
Citations
PageRank
Tudor I Oprea135946.89