Wednesday, 20 September 2017

To logP or logD, that is the question

So last week I asked twitter which lipophilicity measure was more relevant of binding of bases to hERG. The poll resulted in a landslide for logD(pH=7.4) (70%; 21 votes) over logP (30%; 9 votes). I did not vote.

So let's take another look at the question and I've cooked up a thought experiment to help you do this. Let's suppose that we have an amine bound to hERG (which your Scottish colleagues may call hairrg). It has a pKa of 10.4 and logP of 6 and the IC50 in the hERG assay is 100 nM (the safety people think that this will lead to an unpleasant torsades de pointes that will hERG a whole lot more than a corrective thrashing by Wendi Whiplasch). Provided that there is no significant partitioning of the protonated form of the amine into the octanol, the logD(7.4) value for the amine will be 3.

Let's imagine that we can change the pKa of the amine while keeping all the other physicochemical and molecular properties the same. Changing the amine pKa from 10.4 to 12.4 will get logD(7.4) down to 1. But how do you think the hERG IC50 will respond?      

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