Once in a while a collaboration takes you into a whole new domain, in the past few years I feel like I have jumped into the ocean.
One of my long time collaborators Matthew Krasowski from the University of Iowa has been working on the evolution of nuclear receptors. Last year he published a paper on the evolution of FXR, VDR, PXR in the pufferfish and other species in collaboration with many co-authors including Seth Kullman and Erin Kollitz at NC state. What is unique about Matt’s highly collaborative approach is that he uses small molecules, in this case bile salts and synthetic ligands to probe the biological activity profiles of these receptors to understand their evolution. He also included collaborators that developed computational modeling of the proteins (Ni Ai) and the ligands (me) to illustrate differences between binding pockets of the receptors. Pufferfish and zebrafish were found to have very different bile salt profiles and different receptor selectivity that matched the endogenous ligands. Interestingly the pufferfish displayed bile salt profile and receptor selectivity similar to humans.
Fast forward a year and Andrew Fidler and his group at the Cawthron Institute in New Zealand collaborated with Matt to look at the activation of the sea squirt (ciona) nuclear receptors by natural and sythetic toxins, including microalgal biotoxins. This continued some earlier pharmacophore modeling of the cionaVDR/PXRalpha which we had modelled. Two biotoxins activated this receptor and these are much larger than the previous ligands identified as activators. Also one pesticide, esfenvalerate was found to activate it at higher concentrations. The paper proposed the receptor evolved to bind the molecules in the sea squirt diet and because of their ecological niche they may be a useful biosensor.
All of these studies depend on good quality sources of data, whether that is the sequence of proteins for homology modeling, X-ray structures for docking or small molecules for pharmacophore modeling. This blog has extensively covered the idea of the need for a gold standard molecule database. Antony Williams and I were asked to put an online editorial together for Drug Discovery Today. Today this became available and we describe the long term cost of inferior database quality . This topic is becoming something that resonates with me as I go through collaborations like those described above. We are continually building on past data and for our future work, the foundation has to be good. I am grateful to all the collaborators for opening my eyes about new topics and the world around us. The opportunity to integrate experimental and computational approaches, I think is giving us new insights, but we need to make sure that our discoveries are put in good databases for future scientists.