Derek Shore: Allosteric Modulation of the Human Cannabinoid-1 Receptor

Derek Shore, a graduate of UNCG's Doctoral Chemistry program, gave a very compelling lecture that explained the applications and uses of Allosteric Modulation in drug design. His lecture titled,"Allosteric Modulation of the Human Cannabinoid-1 Receptor: Negative Modulators, Positive Modulators, and Everything in Between!" focused on his research project, the creation of a drug that would partially inhibit the effects of inhibiting the CB1 receptor in a manner similar to Rimonabant, but without it's negative side effects. Rimonabant is a diet drug that reduces appetite, however in inhibiting the CB1 receptor, it also leads to depression.

In lieu of finding  that 'perfect' compound, computational physical chemistry was employed. In computational labs, programs such as the Schrodinger Suite were used. These programs apply calculations and formulas that compute the interactions, likelihood, and energy of a compounds in a certain environment. Derek's work focused on ORG27569, an allosteric modulator. An allosteric modulator is a compound that changes the way a receptor interacts or activated indirectly, through modifying the binding site. In Derek's talk he explained some of the processes that he went through in finding the perfect compound and some of the mutations he performed on ORG itself to get some of the unique properties he found.

The calculation that I found to be particularly interesting was the usage of a 'box' in which many calculations were run. The way this worked was that the active site of a receptor was boxed out on the computer program. Calculations on a specific area were run, with certain limitations on how far a compound could occur within the active site. Fragments of the ORG compound were placed within the 'box' and calculated for the likelihood of placement. This created a binding site very similar to Rimonabant, but also distended to the extracellular region. In the distended portion, there was an interaction between the receptor and ORG, which modified a portion of the extracellular looping structure. This had the effect of allosterically modulating the receptor.

I thought that this seminar was particularly interesting because it shows a small aspect of how new medicine and drugs are made. Below are the structures of Rimonabant and ORG27569 respectively.