A very useful list: common linkers and bioisosteric replacements

Last week’s post highlighted an example of fragment linking, which despite being less common than fragment growing can still be effective. But how do you choose the linker? We’ve previously written about the most common rings found in drugs. In a new Bioorg. Med. Chem. paper Peter Ertl and colleagues at Novartis tabulate the most common linkers found in bioactive molecules.

 

The researchers start by defining linkers “as moieties connecting 2 ring systems.” To focus on druglike molecules, linkers could contain no more than eight non-hydrogen atoms total and no more than five consecutive bonds between the two ring systems. This means that para-disubstituted phenyl or 1,4-disubstiuted butyl would both be considered in the analysis, but longer linkers such as this recent example would not.

 

Molecules were extracted from the databases ChEMBL and ZINC, yielding a total of 1686 unique linkers. Various descriptors were calculated for all, which in addition to size and length included the number of heteroatoms and electronic properties. Bioactivity data for molecules in ChEMBL was used to assess which replacements were most frequently tolerated. If one linker could be replaced by another without causing a drop in affinity (or inhibition, etc.), the two linkers were considered to be bioisosteres.

 

So, what are the most common linkers? A single methylene is the most common, followed by an amide bond. I was surprised that, of the 40 most common linkers, only five are rings: para-disubstituted phenyl, 1,4-piperzine, 1,4-piperidine, 1,2,4-oxadiazole, and meta-phenyl, in that order. Not coincidentally, phenyl rings, piperidines, and piperazines are also the most common rings found in drugs, according to an analysis last year.

 

Last year we highlighted a paper from the Ertl group that included a link to a “Ring Replacement Recommender,” which suggests bioisosteric replacements for any ring. Alas, there is no “Linker Replacement Recommender,” but the new paper does provide a “bioisosteric replacement network,” which is a full-page 10 x 15 grid with the 150 most common linkers arranged such that nearby linkers are likely to be bioisosteric. For example, para-phenyl is adjacent to 2,5-thiophene and quite some distance from sulfone. These make sense, but there are also less obvious examples: the table suggests that a 1,4-pyrazole makes a good replacement for a carbamate.

 

The next time you’re doing SAR, it may be worth consulting the bioisosteric replacement network for ideas.