MFernflower
commented
6 years ago A bit unrelated but at some point we should combine the most potent LHS with the most potent RHS - it just so happens that the resultant molecule seems to be in the sweet spot of lipophilicity
www.swissadme.ch is a great free tool for checking predicted ADME features of any molecule you throw at it with out needing to install anything to your machine
@david1597 @maratsydney
This recent perspective article, alongside a comment from the Pfizer team performing our biosynthesis prompted me to look at our series 4 compounds in terms of their lipophilic efficiency. (I found an outdated section on the wiki mentioning LE albiet with very little detail). We're getting decent potency with our current compounds but we need to be very mindful of other factors eg. ADME properties. Varying and optimising the lipophilicity of the analogues we're currently making within our lead syntheses alongside optimizing potency is required. Lipophilicity has been discussed many times before with regards to series 4 eg here, and a good overview of logP/D is given by @drc007 here.
The lipophilic ligand efficiency for the compounds were calculated in DataWarrior using LLE = -log IC50 - cLogP where the IC50 value was the mean IC50 value from the master list. The lipE plot below shows clogP on the x-axis, -log(potency) on the y-axis and is coloured according to lipE value. The structures of the top ranking compounds are shown below that.
This may help us think about the changes we wish to make to our leading potent compounds, especially if we can improve both potency and logP simultaneously. It may also additionally help us identify compounds which have promising lipE but not necessarily the best potency as a separate starting point for further optimization.