08 January 2009

Ligand efficiency for antibiotics

Back in October of last year we highlighted a paper in Science that disclosed a new antibiotic targeting the bacterial protein FtsZ. The compound was derived through fragment-based techniques, though at the time no details were provided. A new paper in BMCL now provides some of the early medicinal chemistry, and also introduces an interesting new tool for evaluating antibiotics.

As mentioned in the Science paper, the researchers (led by Prolysis but with a number of contributors from Evotec and Key Organics) started with the fragment-like (MW = 151, 11 heavy atoms) 3-methoxybenzamide. An initial survey of “SAR by catalog” soon moved to the synthesis of analogs that could be assembled in up to four steps from commercially available compounds. This study found that the amide was essential, and only limited substitutions around the aromatic ring were tolerated. Turning to the alkoxy group, the authors took the classic “methyl, ethyl, butyl” approach, but kept going all the way to dodecyl. Intriguingly, a nonyloxy substituent proved to be optimal, better than either 8 or 10 carbon chains. Adding two fluorine atoms to the aromatic ring improved the potency further. Although the paper does not describe the final push to PC190723, the authors do describe the desire to replace the long alkyl chain and its likely attendant problems.

The paper also defines an interesting variation of ligand efficiency:

Antibacterial efficiency = -ln (MIC) / N, where
MIC = minimum inhibitory concentration (mg/ml) and
N = non-hydrogen atoms

Although the metric has a few quirks (for example, low-efficiency compounds can actually have negative numbers), “good” values correspond roughly to good LE values; clinically approved low molecular weight antibiotics have antibacterial efficiencies in the 0.26-0.32 mg/ml/atom range.

So for all you folks working on antibiotics, not only are fragments a viable starting point, you now have a new way to evaluate progress.


Pete said...

Great to see that the anti-bacterial folk are yet to discover the mole and therefore can give us yet another efficiency metric! I must confess to suffering from 'efficiency metric fatigue'.

I was interested to see that the they used natural logarithms to define antibacterial efficiency. Rather worryingly, they quote units for their antibacterial efficiency of mg/ml per non-hydrogen atom.

Dan Erlanson said...

Pete -

I agree that “antibacterial efficiency” has less physical meaning than “ligand efficiency”: the latter provides a number with units of binding energy per non-hydrogen atom; the former, as you point out, has units that are rather harder to define. Nonetheless, researchers working on antimicrobial research do seem rather wedded to their non-mole based MIC, so an efficiency metric based on this may be more useful to this audience.

And as far as “efficiency metric fatigue” goes, I sympathize, but as you’ll see in the next couple posts there’s still some interesting work being done here.

Pete said...
This comment has been removed by the author.
Pete said...

I forgot to wish you and Teddy all the best for the New Year so have a great one!

Pete said...


My comments on the units of this metric relate to the fact that one only can define a logarithm for a pure (i.e. dimensionless) number and not a quantity like 1 mM that has units. Ligand efficiencies defined in terms of non-hydrogen atoms (NHA) use a logarithm of the ratio of an IC50 to some reference concentration. Any reference concentration can be used to define an efficiency and the numbers you get will be determined by the reference concentration used to define efficiency.


LE = (-log(IC50/ref-conc))/NHA

shows that all LE metrics defined in this manner have units of reciprocal NHA

alex said...

see the development of this project

"An Improved Small-Molecule Inhibitor of FtsZ with Superior In Vitro
Potency, Drug-Like Properties, and In Vivo Efficacy"

Neil R. Stokes et all

Antimicrobial Agents and Chemotherapy
p. 317–325, Volume 57, Number 1