Efficient discovery of inhibitory ligands for diverse targets from a smallcombinatorial chemical library of chimeric molecules

Living systems are mainly composed and regulated by compounds in four bioch emical classes and their polymers-nucleotides, carbohydrates, lipids, and a mino acids. Early combinatorial chemistry libraries consisted of peptides. The present report describes the general bioactivity and biophysical proper ties of a combinatorial chemical library that used glyco, nucleotidyl, and lipid building blocks. The resulting chimeric combinatorial library of 361 compounds had a confirmed cumulative hit rate of 0.16%, which is 8-fold hig her than a commonly claimed industrial benchmark of 0.02%. It produced 7 st ructurally confirmed hits for a third of 12 proprietary drug discovery proj ects, and these comprised a variety of molecular targets. Diversity analyse s demonstrated that despite the small number of compounds, a wider range of diversity space was covered by this library of biochemical chimeras than b y a branched tripeptide library of the same size and similar generic formul a. (C) 1999 Academic Press.