Hit triage, case of MTase

I often see keyword “PAINS” in literature .

Frequent hitters of HTS deck are problematic and PAINS filter is useful to remove them because false positives are time and cost consuming.

Researcher of Lilly, reported nice letter in J. Med. Chem. Lett.

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00375

The author analysed there HTS campaign of Methyltransferases( MTase ).

They screened 9 MTase and NHR, PDE as counter.

I’m interested in Table3 listed in promiscuous MTase Scaffolds.

I thought some scaffolds mimic SAM and maybe theses scaffolds are often show in kinase inhibitors. And I thought it seems good starting point of SAR at first. But it was wrong….

Some compounds shows sub micromolar IC50, but ITC experiments could not detect heat. Also they did HDX experiments and got same results. ( no protein exchange )

It’s worth for me to know that ITC / HDX / SPR or related biochemical assays are useful to pick up real binder.

And author concluded following message.

We hope that sharing our learning from this challenging target class highlights the need for robust confirmation of actives ……… to avoid wasting further resources on likely false positives.

I like the sentence.

Share the knowledge in precompetitive to overcome difficulties. 😉

広告

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