This is the title of a new review published in Trends in Pharmacological Sciences by Christopher Murray, Marcel Verdonk, and David Rees of Astex Pharmaceuticals. Although there is certainly no shortage of reviews on fragment-based lead discovery (a situation to which I have admittedly contributed), this one is notable both for its clarity and for being able to draw upon a deep wealth of institutional knowledge.
The review starts by discussing three notable case studies: Plexxikon’s discovery of the mutant B-Raf inhibitor vemurafenib, Astex’s Hsp90 program, and Merck’s BACE program.
Next, the authors describe some key concepts and challenges of FBLD.
Concept 1: Inappropriate physical properties are a major cause of attrition for small-molecule drugs
This should not come as a surprise to readers of this blog; the discovery of compounds with superior properties is one of the key selling points for FBLD. In support, the researchers compare 39 leads against 20 targets from Astex’s fragment-based programs with 335 published HTS-derived leads and 592 oral drugs. The FBLD-derived leads are on average 62 Da smaller and 1 log unit less lipophilic than are the HTS leads, and are much more similar to the oral drugs.
Concept 2: Although weak in potency, fragments actually form high-quality interactions
The position and the orientation of fragments tend to be conserved during the course of optimization (though see here for a notable exception). Of the 39 internal fragment-to-lead programs, roughly 80% of the atoms in the original fragment (which averaged 13 atoms total) were retained in the lead. Moreover, the mean shift in position as judged crystallographically was only 0.79 Å.
Concept 3: LE can be used to judge the relative optimisability of differently sized molecules
I like to think of fragments as ants: small and weak when considered from a human perspective, but impressively strong when considered for their size. Ligand efficiency and its many permutations are tools to assess molecules in a size-appropriate manner.
Concept 4: Relatively small libraries of fragments are required to sample chemical space
There is plenty of theory to support this (see for example here and here). The authors note that a library of 1000 compounds with 12 or fewer heavy atoms would sample ~0.001% of possible molecules with MW < 170 Da, while 1000 compounds with 25 or fewer heavy atoms would sample only 10-14 percent of the possible larger molecules. But while theory is fine, the real proof is in the number of molecules that have entered the clinic that can trace their origins to small fragment libraries.
Of course, FBLD does have challenges.
Challenge 1: Specialized methods are needed to detect fragment binding
You don’t hunt ants with an elephant gun, and you’ll have a hard time finding fragments using standard procedures. The need for specialized methods was once a major impediment to FBLD, but happily today there are many options, and using two or more of these in combination is the best strategy.
Challenge 2: Efficient optimisation of fragment hits is required
In other words: you’ve found a fragment, now what? Structural biology is extremely helpful to figure out how the fragment binds and suggest what to do next, especially since proteins can be surprisingly flexible: of crystal structures from 25 fragment screens at Astex, 12 proteins showed movement of at least 5.0 Å upon fragment binding.
Of course, it takes more than a crystal structure to advance a fragment, and the challenges can be institutional as much as scientific. But given the proven success of the technique, these are challenges worth facing.
Finally, it’s worth checking out the entire issue of Trends in Pharmacological Sciences, which is devoted to structure-based drug design. There are some nice papers by Zhaoning Zhu on BACE, Tom Blundell and colleagues on protein-protein interactions, Stephen Wasserman and colleagues on high-throughput crystallography, and lots more.