In medicinal chemistry, chemists often make compound analogue which differ only a part. Optimization of R1, R2 etc… After optimized each R group, combination strategy is tried because it is expected that combination make additive effect for potency. But sometime combination strategy doesn’t work well.
To understanding the phenomenon structural information is important. And recently I read interesting article about nonaddtive SAR published in 2018. The URL is below.
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.8b00713
The author analyzed PDE2 inhibitor SAR. They investigated analogue SAR and found that the best R1 and R2 group didn’t generate high potent compound. An example of non additive SAR is shown below.
It is interesting for me that for this scaffold R1 and R2 don’t interfere each other in compound based global minimal conformations. From ligand-protein co crystal based analysis revealed that each substituent interacts same residues and thus steric clash is caused when R1 and R2 are bulky group.
If project can use x-ray information medchem can get useful information about non additive SAR. But a target which is difficult to get x-ray information, how to rationalize non additive SAR. It’s difficult I think but it is important that make hypothesis to explain SAR. To do that I need to read lots of publications to know many interaction pattern.
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