Docking-based virtual screening (VS) methods usually require a high-quality crystal structure of the target protein. The structure, however, may not always be available or not suitable for docking. In this study, we have examined the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), which is one of the three identified primary unfolded protein response (UPR) transducers and can be a potential target for new cancer therapies. The available apo crystal structure of PERK shows a closed Gly-rich-loop at the ATP-binding site of the kinase. This closure is believed to be responsible for blocking the ATP-competitive inhibitors to be correctly docked into the binding site in docking-based VS. Two approaches, which can potentially resolve this issue, are thus examined and validated by comparing with the experimental kinase assay result. The first approach features the application of a model structure, whcih is refined by molecular dynamics simulation, in docking. The second approach takes the advantage of the ligand-based pharmacophore model, thus avoided the kinase structure in VS. Results indicate that docking using the MD modeled structure generally gives twice of the enrichment in VS than using the apo crystal structure. The pharmacophore approach reduces the computing cost by thousands-fold over docking while giving comparable enrichment as docking. Additionally, re-ranking of the pharmacophore result using docking scores gives a slightly better prediction over using either approach alone.  Therefore, we anticipate that such a combined approach may be served as a more cost-effective way in screening large databases that of millions of compounds.

Virtual screening of PERK inhibitors

246th National Meeting (2013)

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