I was looking through recent literature this past week and found a few things in JACS that I thought were particularly interesting.

The first comes from Kelly Damm and Heather Carlson, and substantiates my feeling that NMR is the coolest technique ever invented. In this case, they were trying to figure out the best way to incorporate protein flexibility into structure-based drug design. The authors previously established an MD method to generate multiple protein conformations of a single protein; the resultant ensemble worked better in assigning known inhibitors or non-inhibitors appropriately than a static structure. But all those calculations take a lot of time, and so Damm and Carlson went to the pdb, pulling out 90 static structures of HIV-1 protease (bound to a variety of ligands) and one NMR structure, which is actually an ensemble of 28 structures. What they discovered is that the success of these two ensembles was quite similar in identifying inhibitors, but that the NMR structure was less specific to a given ligand and so was more able to identify the essential features of the ligand and extrapolate to new classes of compounds. So, they suggest NMR structures as useful tools for SBDD. Go NMR!

Two communications also caught my eye: one, from Scott Miller’s group, extends his work on small, peptide-based catalysts to an Asp-catalyzed asymmetric epoxidation. In this case, putting the Asp carboxylate into a protected tripeptide known to form beta-turns resulted in a catalyst that could turn over nearly 20 times, with 97% yield and 92% ee in optimized conditions. He wrote a nice review on the rationale for this work now three years ago, but I would still recommend it. The second is work from John Klassen’s lab: Amidst the ongoing controversy of what gas-phase analysis of proteins really means, they seem to have put together a nice method for monitoring ligand binding sites, and determining whether the sites are identical (linear slope of ligand released over time and temperature) or not (non-linear slope).

Well, that’s my weekend reading. Now back to watching Wimbledon…

(ed’s note: Dr. Carlson alerted me to the fact that the study was actually about HIV protease, which I fixed 07/05)

Catherine (associate editor, Nature Chemical Biology)

It’s double-blind or nothing when it comes to phase III clinical trials. Although placebo groups are absolutely vital to the clinical validity of medical treatments, a recent article in The Lancet has me thinking about the ethics of treating desperate patients with saline.

The subthalamic nucleus is overactive in people with Parkinson’s disease, presumably because it loses GABAergic input from the globus pallidus. Subthalamic nucleus lesions improve Parkinson’s disease symptoms. Kaplitt et al. generated a gene therapy agent that would silence but not destroy subthalamic nuclei neurons. They inserted glutamic acid decarboxylase (GAD), the enzyme responsible for GABA production, into a viral vector and injected it into subthalamic nuclei of people with Parkinson’s disease. In their phase I trial in 12 patients, the authors showed that their therapy was safe and virtually side-effect-free. Unlike most phase I trials, the authors also showed that their treatment was effective: intra-thalamic injections of the GAD agent reduced Parkinson’s symptoms.

That’s great news for a possible new treatment for Parkinson’s disease. But it also means that at some point soon, people with advanced Parkinson’s symptoms will volunteer for brain surgery and a 50% chance at treatment. Some would argue that even placebos have their upside, and I certainly understand their importance. I also understand that the patients who volunteer for these studies are often at the end of their medical ropes and are willing to roll the dice. I just feel for the folks who wake up 6 months after surgery and realize that their symptoms haven’t improved.