Redox potentials and drug discovery

A paper just out, that set me thinking a bit about are we missing a trick or two, discusses redox potentials of hydroxycinnamic acids such as caffeic and ferulic acid this are of particular current interest in health because of their anti-oxidant activity. It’s estimated that this class may constitute one third of the phenolic compounds in our diet. The paper determines redox potentials for a range of these acids alongside their antioxidant activity showing that they correlate with each other and allows development of structure property activity relationships.

All this is well and good assuming stuffing ourselves with anti-oxidants really is a good thing, though I will keep drinking the red wine just in case, but what about use of redox potentials more generally in drug design – are we missing a trick. My past experience and from what I see in the literature I generally read is very little use of the technique to help understand how our molecules will behave – when I tried to get some redox potentials measured while working in big pharma I was told the kit was no longer available – note the no longer. I guess where I am coming from is can we use measured redox potentials as part of our understanding of improving stability of molecules in aggressive redox environments particularly within metabolic enzymes. A quick look on google did pick up this thesis sponsored by Roche looking at developing high throughput redox measurement techniques. The starting point they come from is that redox potentials can be considered equivalents of ionisation potentials. So could we be looking at some sort of cascade of calculated ionisation potentials during in silico design followed by redox potentials after synthesis and who knows perhaps exploit electrochemistry during synthesis another under used area perhaps? It would be good to hear people’s thoughts on this.


Dimorphism matters

While I suspect most people working in drug discovery are aware of gender differences in the way drugs can behave in the clinic, dimorphism in cells is perhaps less well recognised. A Nature comment from Elizabeth Pollitzer highlights the importance of recording the gender of cells in experiments citing examples of differences in response of muscle derived stem cells from male and female subjects and responses of cells to stress. Dr Pollitzer also notes that ten prescription drugs were withdrawn between 1997 and 2001 due to gender differences in adverse events a figure which did surprise me a little. While hormonal differences can explain some differences in both exposure and efficacy/safety others have been attributed to differences in metabolic pathways.

Thinking within the context of a drug screening cascade at what stage should one be checking for dimorphism –Dr Pollitzer recommends ideally running separate cell based studies from both males and females which seems very reasonable. Perhaps (and admittedly much more demanding) does this need extending to the in vivo situation running male/female PK/PD, on late leads, at least where other evidence suggests this may be appropriate. From a metabolic perspective, one thing I am not clear about with microsomal studies – are pooled microsomes or hepatocytes pooled from both male and female or from single gender. Will we see drugs being developed which only achieve exposure/efficacy in one gender – clearly I am not considering treatments for more obviously gender specific diseases here?  Perhaps also we may see an improvement of reproducibility of experiments from the literature if (again as Dr Pollitzer urges) journal editors and referees insist on the reporting of the source gender of cells

Finally in similar vein reinforcing the importance of recognising and understanding gender differences two EU reports. The first on gendered innovations that considers where there may be opportunities for innovation based on gender biases in population analysis – eg in cardiovascular disease historically it has been mainly males that have been studied – is this information as relevant to the female as the male? The second I guess reinforces the first by emphasising that the absence of thought about dimorphism in running and reporting of experiments is a bigger concern than any funding or recruitment gender inequities.