In silico Studies Toward the Discovery of Novel Type-II Inhibitors of TrkA: Pharmacophore-based 3D-QSAR Modeling, Database Screening and Molecular Docking
Publisher:
Bentham Science Publishers
E-ISSN:
1875-628x|13|6|526-538
ISSN:
1570-1808
Source:
Letters in Drug Design & Discovery,
Vol.13,
Iss.6, 2016-06,
pp. : 526-538
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Abstract
Tropomysin receptor kinase A (TrkA) is an excellent drug target for its important roles inpain sensation as well as tumour cell growth. Up to now, the discovered TrkA inhibitors belongmostly to type-I class targeting the ATP binding site, while we aim to find type-II inhibitors becausethey are deemed to have improved kinase selectivity and slower off-rates than their counterparts. Thetype-II inhibitors can induce TrkA in an inactive DFG-out form and insert in an additional hydrophobiccavity adjacent to the ATP binding pocket. The current article describes efforts to discover noveltype-II scaffolds against TrkA via integrating pharmacophore-based 3D-QSAR modeling, databasescreening and molecular docking. The robustness of the best model, AAHRR.8, was seriously ascertainedby the high R2 (0.9027), Q2 (0.7048), low RMSE (0.4016) and SD (0.3635). It was further usedas a 3D query to screen against our in-house collection of almost 1.3 million compounds followed by molecular dockingsimulations using three docking protocols involving Glide SP, Surflex and Glide XP. 12 hits, which mapped well on thebest pharmacophore model, displayed good docking score and rational binding mode, were selected as promising selectiveleads of TrkA. Finally, ADME study was carried out and the results indicated that these 12 compounds own drug-likeproperties. The 12 hits together with the best 3D-QSAR model will be helpful for future potent TrkA agent development.