Do rapid SAR iteration!

Now I participating with JCUP, it is exciting for me. Due to growing the computer performance such as GPU computing, in silico technology become very powerful method in drug discovery.
And also DMTA cycle is going to next stage. You know recent publication from Merck is amazing for me. They make thousands of molecules on very small scale and perform their assay in crude state.
https://www.nature.com/articles/s41586-018-0056-8
There is nice review regarding the article. So I would like to post another approach for rapid SAR.

Here is report from Cyclofluidic.
https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b01698
Their unique feature is closed-loop structure activity platform, to revolutionise hit and lead optimisation. In the article they explore SAR of Hepsin, a membrane-anchored serine protease.
The compounds are build from three parts acyl/sulfonyl, amino acid and guanidino protease catalytic domain has the catalytic triad of His, Asp and Ser residues. It indicates that guanidino residue is necessarily to keeping activity.

The author explore SAR with flow chemistry. They changed synthetic flow compared to batch synthesis, used TMS protected amino acid for flow chemistry because free amino acid shows low solubility and it is problematic factor. It is good tips for flow synthesis.

Finally they obtained highly active and low toxic molecules. It seems success story of the technology. BTW, I wrote below, to keeping the activity guanidino moiety is required. And it shows bad effect for ADMET profile especially permeability.
I think low cell toxicity comes from this low permeability. Of corse this target is trans membrane and does not need to going to cell inside. But low permeability is not good feature for drug (my opinion).
I am interested in next action of the research.
I think Cyclofluidic technology is very interesting and useful for rapid SAR.
How about readers opinion. ;-)

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Published by iwatobipen

I'm medicinal chemist in mid size of pharmaceutical company. I love chemoinfo, cording, organic synthesis, my family.

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