A novel approach to combinatorial library design.
We address the problem of designing a general-purpose combinatorial library to screen for pharmaceutical leads. Conventional approaches focus on diversity as the primary factor in designing such libraries. We suggest making screening libraries out of a set of pharmaceutically relevant scaffolds, with multiple analogs per scaffold. The rationale for this rests on the fact that even though the hit-rate in active series is much higher than in the database as a whole, often a large fraction of the compounds in active series are inactive. This is especially true when the series has not been optimized for the target under study. We introduce the concept of  hit-rate within a series  and use historic screening data to arrive at a crude estimate for it. We then use simple probability arguments to show that 50-100 compounds are required in each series in order to be nearly certain of finding at least one active compound in each true active series for any given target.
Nilakantan
Ramaswamy
R
Computational Chemistry, Wyeth-Ayerst Research, Pearl River, New York 10965, USA. Nilakar@war.wyeth.com
Immermann
Fred
F
Haraki
Kevin
K
D002626:Chemistry, Pharmaceutical; D020650:Combinatorial Chemistry Techniques