Many studies published in the last few years have demonstrated that in general, ligand-based methods are better for virtual screening compared to structure-based docking methods. For example, a 2007 Merck study showed that 2-D similarity searching methods are quite good for finding similar leads, while 3-D methods can do some scaffold hopping and find new families of structures. Both methods are generally superior to docking. One of the reasons for this is that docking is not really designed for virtual screening; docking is much more valuable for prediction of crystallographic conformations and most importantly, predicting binding affinity, which is the holy grail of the industry. The latter task is still extremely challenging, although dents have been made in tackling it.
In any case, so this group from Vertex tackled a kinase inhibitor search problem for Pim-1 kinase using docking, and this seems to be one of those cases where docking with Schrodinger's Glide program helped complement and indeed improve upon HTS. The group screened a large database enriched in kinase inhibtors by HTS and got only a 0.3% hit rate. They decided to find out if VS could do better. They used Glide to screen a corporate collection that was less enriched in kinase inhibitors, to avoid bias. They used Glide not in the VS mode but the regular docking mode which takes more time but is more accurate. They used some astute filters to avoid getting false hits from large molecules that fit better in the site. They also used an C-H aromatic hydrogen bond constrain in the docking.
After screening out compounds that were too large and hydrophobic, they got 4 compounds (a 4% hit rate) with activities ranging from 90 nM to 550nM. Two of these could be crystallised and it was confirmed that the experimental conformation was very close to the predicted binding conformation. Glide also picked up the "weak" C-H aromatic hydrogen bond. The authors conjecture that the reason why Glide chose this H-bond is because the traditional hinge region of Pim-1 kinase is more hydrophobic than that in other kinases because of a proline residue. The study demonstrates how VS can serve as a valuable complement to HTS.
Pierce, A.C., Jacobs, M., Stuver-Moody, C. (2008). Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase. Journal of Medicinal Chemistry DOI: 10.1021/jm701248t
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