Wet and dry: or how I left the bench and started to love the blobs

I have never really thought to analyze why I shifted from doing ‘wet’ science at the bench to  ‘dry’ science in front of a computer. A trip to get a flu shot this weekend brought it all back. A relatively simple question “do you have a latex allergy”? Well yes my hands crack after wearing latex gloves and that last happened in 1996. Since then it’s been nitrile ones for me (but..why always blue?).

My last wet science was as a postdoc in 1998. I probably thought in 1996 as I began I would always be at the bench but one talk at an ISSX conference in San Diego gave me pause for thought. The speaker – and to this day I am not sure who it was, presented some computational models of a Cytochrome P450. I had seen such homology models in papers before but this time it was different. In science I have found timing is everything and this was one of those perfect coincidences. To this point I had spent 6 months characterizing a minor human P450 called 2B6. Kind of like a second string actor, small roles, occasionally important, never gets the girl, overlooked for an Oscar, do you get the picture? I had tried building up a set of a few (a handful- years before high throughput screening) substrates and thought I was done, even started thinking about getting a real job..The talk made me think maybe I can create a computer model with my data and that would help model the substrate requirements for the enzyme and find others. Going back to the lab, I mentioned the idea and the director drug Disposition at Lilly then, Pat Murphy put a call (better than email) into his friend in the computational group Jim Wikel. Jim agreed to chat with me and that’s how in late 1996 I came to start to use computers to do scientific research and gained a second mentor.

Those were the days when molecular modeling graphics software ran on incredibly pricey Silicon Graphics machines ( cute names like Indy and Octane) and the software itself was not cheap either. Jim sat me down and showed me how to build pharmacophores (key chemical features in molecules for activity) with software called Catalyst from a company called MSI (now Accelrys). I was hooked immediately. You drew in the 2D structure of a molecule, created 3D conformations, created a spreadsheet of the molecules and bioactivity and then let it go calculate a model. Several hours later if you were lucky it would return several models and a correlation. The models were nothing more than spheres (blobs) with vectors for direction of chemical features like hydrogen bond acceptors or donors.  Once you had a model you could draw in new molecules, calculate 3D conformations and predict affinity et voila, in silico predictions or as I called it “Silicon CYP.” Back then we also had to take photos of the pharmacophores for publication in papers – sending glossy shots of blobs for inclusion in manuscripts- seems almost as archaic as punch cards for programming computers. I have never needed or wanted to play computer games since, as software has allowed me to try to understand pharmacology at the molecular level. Reality via models being way more interesting than virtual worlds for me.

Put simply, thus began what is now a 16 yr voyage of scientific discovery with blobs. Along the way I have discovered pharmacophores for not only P450 2B6, but an array of other enzymes, nuclear receptors, ion channels and drug transporters. Simple blobs were the bait that hooked me on using other types of computer software or algorithms and now have me using mobile devices to do cheminformatics. Initially I still generated wet data myself but as the years have gone by, collaborations with scientists allowed me to model full time and get me into other areas of computational drug discovery. As time went on it became key to validate the models prospectively, but that can be for future blogs on using wet and dry science together.

Sometimes conference talks give me good ideas, in this case it helped change the course of my research, took me away from the bench and requirement for gloves. Who knows what will be next. More blobs?  perhaps something else will inspire me at the next conference and after that who knows where it will take me?



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