Docking and chemoinformatic screens for new ligands and targets.
Computer-based docking screens are now widely used to discover new ligands for targets of known structure; in the last two years alone, the discovery of ligands for more than 20 proteins has been reported. Recently, investigators have also turned to predicting new substrates for enzymes of unknown function, taking docking in a wholly new direction. Increasingly, the hit rates, the true-positives, and the false-positives from the docking screens are being compared to those from empirical, high-throughput screens, revealing the strengths, weaknesses, and complementarities of both techniques. The recent efflorescence of GPCR structures has made these quintessential drug targets available to structure-based approaches. Consistent with their 'druggability', the docking screens have returned high hit rates and potent molecules. Finally, in the last several years, an approach almost exactly opposite to docking has also appeared; this pharmacological network approach begins not with the structure of the target but rather those of drug molecules and asks, given a pattern of chemistry in the ligands, what targets may a particular drug bind to? This method, which returns to an older, pharmacology logic, has been surprisingly successful in predicting new 'off-targets' for established drugs.
Kolb
Peter
P
Dept of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th St., Byers Hall Room 508D, San Francisco, CA 94158-2550, United States.
Ferreira
Rafaela S
RS
Irwin
John J
JJ
Shoichet
Brian K
BK
D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure
D008024:Ligands