Drug repurposing database
Drug repositioning: similar sites are likely to bind the same ligand
Repurposing tested small molecules drugs for new indications or new mechanism of action is an appealing strategy. MED-SuMo can be used in cases where a drug is co-cristalized with its target. If a similar binding site can be found in the Protein Data Bank  (or any macromolecule structure database), it is likely that this drug would also bind to this similar target. This target hopping case is on one hand probably rare but, on another hand, could be a strong rational evidence to highlight a possible off-target and eventually a possible undesired side effect. During lead discovery for a new target, finding cross-reactivity to a target for which there are already leads, enables the fast discovery of new leads via target-hopping. With the potential of short-circuiting the lead discovery process on a genomic scale, target hopping is an important chemogenomic application of structural informatics.
MED-SuMo is used in Site vs Binding Site database to find in the PDB the most similar sites to B-RAF/sorafenib
This case study is about an example of repurposing sorafenib from B-RAF to others protein kinases. The B-RAF-sorafenib complex 3D structure is available in the PDB (code 1UWH ) and is used as the input of MED-SuMo to query the PDB binding site database. The database is redundant in terms of unique site or pocket but very interestingly for our application, it is exhaustive in term of kinase conformations and bound ligands.
Fig1: The input of MED-SuMo: 58 Surface Chemical Features (rendered as colored ball and stick) in the 6 Å vicinity of sorafenib in the B-RAF-sorafeninb complex (PDB code 1UWH). The backbone of B-RAF is shown in grey (only the secondary structure is shown) ; the DFG-out ligand, sorafenib is rendered as sticks.
The top results are shown in the screenshot of the result table: top hits are mostly DFG-out protein kinases followed almost exclusively by protein kinases. MED-Sumo identifies the most similar protein kinases binding sites (about 1/5 of all protein kinases), together with a few ATP binding proteins. The results are very different from a sequence based search tool where all protein kinases would be found first.
A simple measure of similarity between the site hit and the query site is obtained by normalizing the score of the hit to the maximum possible score (site query towards itself)).
Relative MED-SuMo score (%) = Hit score / Query score * 100
In this case study, we show that target hopping is likely to occur above a relative MED-SuMo score of 60%: the first hit which is not a DFG-out kinase is a DFG-in protein kinase: 3C4C ranked as the 33th hit. The relative score is 54% which makes sense as the DFG-in and the DFG-out binding mode share the hinge and the gatekeeper region which is about 50% of the pocket.
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