Successful fragment-based lead discovery typically starts with a good library. But what is “good”? Given that most fragment libraries are small, diversity is generally prized. The idea is to cover as much chemical space as possible with the fewest molecules. When most chemists hear the word diversity they think of structural diversity; tetrahydrofuran looks quite different from pyridine, for example. Functionally though, both contain a hydrogen bond acceptor. In a paper recently published (open access) in J. Med. Chem., Charlotte Deane and collaborators at University of Oxford and Diamond Light Source argue that functional diversity is more important.
Frank von Delft and his XChem colleagues at the Diamond Light Source have been screening dozens of targets crystallographically, many of them using the DSI-poised library, designed to enable rapid elaboration of hits. (We described it here). For the present analysis, the researchers considered ten diverse proteins (maximum pairwise sequence identity of 27%) that had all been screened against 520 fragments. Of these, 225 bound to at least one target.
The researchers considered what types of interactions the bound fragments made with the protein at either the residue or atomic level. For example, a fragment might serve as a hydrogen bond acceptor to the hydroxyl group of a serine residue. These interaction fingerprints, or IFPs, were calculated and compared.
Interestingly, there was no correlation between fragments that made similar IFPs and their structural similarity. In other words, “structurally dissimilar compounds can exploit the same interactions.” Moreover, many different fragments made similar or identical interactions: “structurally diverse fragments can be described as functionally redundant.”
In fact, just 135 fragments could make all the interactions observed for the 225 fragments. Some made more novel interactions than others, with “promiscuous” fragments that bound to multiple targets tending to be more informative.
The top 100 of these 135 functionally diverse fragments tended to have molecular weights between 175 and 240 Da and 12 to 16 non-hydrogen atoms, putting them comfortably within rule of three space. Interestingly, fragments that never hit any target skewed smaller, with many having molecular weights less than 175 Da and fewer than 12 non-hydrogen atoms; this is slightly at odds with work from Astex which found many tiny fragment hits.
The researchers considered sub-libraries consisting of either these functionally diverse fragments, randomly selected fragments, or structurally diverse fragments. The number of interactions discovered was significantly higher for the functionally diverse sets of fragments than for the other sets.
On one level the findings are not surprising: the whole concept of bioisosterism relies on the fact that different functional groups can make the same interactions, meaning that structurally disparate fragments can be functionally redundant. This suggests that libraries could be optimized to capture more information with fewer molecules. How to do so prospectively is not entirely clear, but laudably the researchers have provided chemical structures for all the fragment hits in the Supporting Information. It may be worth adding some of the functionally diverse fragments to your library; perhaps some enterprising vendor will start selling the top 100 as a set.