No love for the medium-sized molecules?

From my guest column at the Biophysical Society Blog.

Like a few others posting on this site, I had the pleasure of presenting a poster during one of the poster sessions yesterday.  I was slotted into the “Protein – Small Molecule Interactions I (Late)” session which the powers that be decided my subject matter was the most appropriate for.  The (Late) was of course due to my own tardiness in applying to BPS 2015– since this is my first big conference, my excuse is that I’m not used to planning so far in advance, as my lab’s administrative assistant who had to book my hotels last week can surely attest.

I’ve been told that in previous years the poor unfortunate souls with a late abstract for BPS were all piled into a single poster session at the end of the last day of the conference, leading to a jumble of different subjects in one place and a dwindling concentration of passers by.    This year’s implementation was great, with a selection of late posters in each subject area presenting in various sessions throughout the week.  The traffic was high, and I was delighted and challenged by the discussions that tended to follow my poster spiel.

Since I’m an engineer (undergrad) and applied physicist (PhD) trying to make my way in the field of drug discovery and designer therapeutics, I sometimes feel a bit like a fish out of water when surrounded by peers with more formal training in organic chemistry, pharmacology and drug discovery.  This has never been more obvious to me than during this poster session with visits from and discussions with scientists from leading organizations as Pfizer, Roche, and Novartis.  I think I managed the much appreciated but challenging interest from these questioning individuals, but I couldn’t help but get dragged into the middle of an argument (perhaps better stated as a polarizing discussion) with my questioners: Small molecules vs. Biologics.

This was a difficult situation to be in, especially as the focus of my research is the characterization and discovery of conformationally constrained peptidomimetics — which are neither small molecules or biologics — a type of medium molecule, if you will.  Small molecules (the subject of the poster session I found myself in) usually follow Pfizer’s rule of five, which limits the number of hydrogen bond donors/acceptors (5/10), gives a molecular weight limit (500 Da) and an octanol partition coefficient (5).  These types of molecules tend to work well as drugs, and in the pharma industry, lead compounds are rarely pursued if they don’t satisfy most of these rules.  Small molecules tend to passively diffuse into cell membranes, have a high chance of oral bioavailability, and have good pharmacokinetics.  To effect a biological process, these molecules generally find a hydrophobic binding pocket (or thermodynamic sink) on a protein’s surface.  Biologics on the other hand are macromolecular biological molecules like proteins or DNA extracted or manufactured from a biological source.  These molecules tend not to be orally bioavailable, and do not passively enter cells, but do not require a binding pocket and often (in the case of antibodies) their high affinity and steric bulk is used to effect a biological process.

Many of the perusers of my poster were well aware of these distinctions, and used the opportunity of my presentation to trade barbs with one another as to the relative merits of each side.  I found myself in the middle on an uphill battle to convince both sides that a compromise existed staring them in the face.  Did I succeed? We’ll see.  I handed out some cards and we’ll see if anyone comes calling.