Tuesday, 20 January 2009

Molecular Complexity (follow up)

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Dan Erlanson, who needs no introduction in this forum, commented on the previous post. I have to agree with him that the Hann complexity model is not easy to apply in practice. It predicts that there will be an optimum level of complexity for a given assay system (detection technology + target) but doesn’t really tell us where a specific combination of molecule and assay system sits relative to the optimum.

Screening library design, as Dan correctly points out, involves striking a balance. One needs to think a bit about screening technology and the likely number of compounds that you’ll be screening. Another consideration is whether the screening library is generic or directed at specific targets or target families. I’m very interested in screening library design and expect to post on this topic in the future.

Dan notes that low complexity molecules often don’t find favour with medicinal chemists and I‘ve experienced this as well. Having structural information available gives us confidence to do something other than what a former MedChem colleague called ‘pretty vanilla chemistry’. Put another way, to make the most of the output from fragment screening, the medicinal chemist needs to be seeing a phenyl group as a synthetic handle

3 comments:

Molecular Simpleton said...

Peter - glad to see the old paper having some air time! One thing that I could add is around how to think of Ligand Efficiency within our model. My way of thinking of this is that the probability curve for the chance of detection (the one that goes from 0 to 1) is moved to the left for more ligand efficient compounds. ie there is a higher chance of the measurement (by whatever method you choose) working for a less complex compound. The effect of this on the "chance of useful event" curve is also to move it to the left and most importantly to increase its value so there is a higher chance of the useful event. One day I hopet to get to putting this in a paper of follow up thoughts but in the meantime will share with this new community in the hope of provoking some more discussion! Mike

Syn-chemist said...

Though I am new to this field. Its really interesting info. I was trying to understand FBDD, HTS and compare these two aspects of drug discovery. Thanx for the detailed info....

Syn-chemist said...

Thanks for ur invitation and the info is really interesting about FBDD and as I wanted to compare HTS and FBDD., really helpful. Thanx. Pete.