The synergy between combinatorial chemistry and high-throughput screening.
Despite the initial promise of combinatorial chemistry, particularly large library combinatorial chemistry, to greatly accelerate drug discovery, this approach has not been fully utilized as a means to build the compound collections of pharmaceutical and biotechnology companies. This review highlights some of the strengths of large library combinatorial chemistry as a means of generating molecules for lead discovery, such as providing rich and robust structure-activity relationships around each hit series. The challenges and concepts emerging from traditional high-throughput screening and fragment-based drug design, how these methods influence the design of large combinatorial libraries and the interpretation of the ensuing high-throughput screening data are also highlighted.
Diller
David J
DJ
Department of Molecular Modeling, Pharmacopeia Inc, CN5350, Princeton, NJ 08543, USA. ddiller@pcop.com
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011962:Receptors, FSH / Q000819:agonists / Q000737:chemistry; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods*; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry
D008024:Ligands; D047428:Protein Kinase Inhibitors; D011962:Receptors, FSH; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D014227:Triazines; D048051:p38 Mitogen-Activated Protein Kinases