Turning a false-positive into an active

People who deal with molecular recognition are well aware of what difference a small modification to a molecule can make. Just today I was attending a talk by a chemist who binds small molecules to RNA aptamers. He showed an aptamer that binds theophylline with 10,000 fold more affinity by caffeine- a huge difference in binding affinity for a molecule differing by only one methyl.

So it is also for medicinal agents, as demonstrated below for an example from the cited study. People who do screening must always have this nagging doubt about false positives; what if there is only a slight modification to a false positive that will convert it into an active?



Bill Jorgensen's group has done a similar study for an anti-RT HIV inhibitor. He first did similarity searching with the Maybridge library based on six known NNRTI inhibs of RT. Based on this, he found a couple of molecules in the library which he then docked into the active site of RT using the program GLIDE. Along with the six known inhibitors which scored at the top as binders, he also found one from the library. GLIDE had already been benchmarked by reproducing known crystallographic conformations.

However, when they tested this GLIDE ranked molecule against HIV, it was disappointingly inactive. On the other hand, perhaps, since GLIDE had docked it up there with the known actives, there might be a small modification that one could make to it which would inject some activity in it? Jorgensen's group used a program that they have developed named BOMB, which basically docks a molecule in an active site, and then grows appendages to it to see if it would make a difference in the binding affinity. BOMB tried out combinations of different groups on the phenyl ring of the molecule, scored the resulting structures using its energy function, and finally settled on one particular modified structure- also filtered by logP values and other Lipinski considerations- that eventually gave an IC50 of 300 nM. Not a fantastic number, but good enough to pursue as a lead.

Also noteworthy in the paper is a short discussion of another publication where a similar structure was published. According to the authors, the other authors assayed the wrong compound. Heh.

Reference:
From Docking False-Positive to Active Anti-HIV Agent
Gabriela Barreiro, Joseph T. Kim, Cristiano R. W. Guimarães, Christopher M. Bailey, Robert A. Domaoal, Ligong Wang, Karen S. Anderson, and William L. Jorgensen
Web Release Date: 06-Oct-2007; (Article) DOI: 10.1021/jm070683u