Structure-based virtual screening of Src kinase inhibitors.

Article Details


Lee K, Kim J, Jeong KW, Lee KW, Lee Y, Song JY, Kim MS, Lee GS, Kim Y

Structure-based virtual screening of Src kinase inhibitors.

Bioorg Med Chem. 2009 Apr 15;17(8):3152-61. doi: 10.1016/j.bmc.2009.02.054. Epub 2009 Mar 5.

PubMed ID
19321350 [ View in PubMed

Src is an important target in multiple processes associated with tumor growth and development, including proliferation, neovascularization, and metastasis. In this study, hit identification was performed by virtual screening of commercial and in-house compound libraries. Docking studies for the hits were performed, and scoring functions were used to evaluate the docking results and to rank ligand-binding affinities. Subsequently, hit optimization for potent and selective candidate Src inhibitors was performed through focused library design and docking analyses. Consequently, we report that a novel compound '43' with an IC(50) value of 89 nM, representing (S)-N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)-7-(2-methoxyethoxy)quinazolin-6- yl)pyrrolidine-2-carboxamide, is highly selective for Src in comparison to EGFR (IC(50) ratio>80-fold) and VEGFR-2 (IC(50) ratio>110-fold). Compound 43 exerted anti-proliferative effects on Src-expressing PC3 human prostate cancer and A431 human epidermoid carcinoma cells, with calculated IC(50) values of 1.52 and 0.78 microM, respectively. Moreover, compound 43 (0.1 microM) suppressed the phosphorylation of extracellular signal-regulated kinases and p90 ribosomal S6 kinase, downstream molecules of Src, in a time-dependent manner, in both PC3 and A431 cell lines. The docking structure of compound 43 with Src disclosed that the chlorobenzodioxole moiety and pyrrolidine ring of C-6 quinazoline appeared to fit tightly into the hydrophobic pocket of Src. Additionally, the pyrrolidine NH forms a hydrogen bond with the carboxyl group of Asp348. These results confirm the successful application of virtual screening studies in the lead discovery process, and suggest that our novel compound 43 can be an effective Src inhibitor candidate for further lead optimization.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BosutinibProto-oncogene tyrosine-protein kinase SrcIC 50 (nM)1.2N/AN/ADetails
DasatinibProto-oncogene tyrosine-protein kinase SrcIC 50 (nM)14N/AN/ADetails
DasatinibProto-oncogene tyrosine-protein kinase SrcIC 50 (nM)0.6N/AN/ADetails