Predicting Off Target Hits in Drug Discovery

Screening Mutiple Binding Sites for Drug of Sunitinib

• Sunitinib is a drug approved by the FDA on January 26, 2006, which is for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST).
• Sunitinib has multi-targeted receptors, (RTK, KIT and PDGFR inhibitors etc.)
• Sunitinib with KIT protein receptor has 3D structure in PDB (3G0E)
• The images of molecule, protein and binding site are displayed below.
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• Sunitinib binding site in 3G0E can be described by PFSC below.
• The binding pocket is described by three fragments
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• With Probe Binding Site for Drug Discovery (PBSDD) technology, starting from Sunitinib binding site, the PF-PDB database was screened.  About 85,000 protein structures were screened to find out the similar binding site as Sunitinib. >
• All results were ranked according the similarity score of PFSA-S and physiochemical property.  
• Only structures on top of 85,000 protein structures were selected as higher similarity, which predicted potential binding sites for Sunitinib. Part results are shown below.
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• amples of the fingerprints of binding sites
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• Samples of alignments for structures with higher similarity score
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• From 200 structures with higher similarity score among 85,000 protein database (0.21%), hit targets were summed as below chart.
• Top of chart shows the protein receptors which are detected by bio-assays. It is important that PBSDD result also hit most of these targets.
• Bottom of chart is new target which predicted by PBSDD technology here.
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