Design of Bioisosteres: Make Ways to Rational Design

Bioisosteres are useful sets of tools for medicinal chemistry so as to endow a hit or the lead to possess the requisite pharmacokinetic and pharmacodynamic property with high activity and selectivity. As discussed in our blog,¹⁾ bioisosteres of prevalent chemical structures are still developing.

However, it is often the case with a medicinal chemist to design and figure out a new bioisostere. It is because multiple parameters are deeply related to chemical and biological equivalency. Well-known bioisosteres are given birth to by an intense trial and error over the history of molecular and drug design.

It will be a huge impact if rational switch of a chemical structure of interest or even a series of structures to the bioisosteres. This technology undoubtedly improve the efficiency and shorten the timeline of drug development.

With a lot of manpower, novel bioisoteres have been developed. Recent example of a bioisostere of the phenyl ring is reported in nature communications.²⁾ The authors took 2-oxabicyclo[2.2.2]octane skeleton as the mimic of phenyl. Although bicyclo[2.2.2]octane and cubane skeletons were known, the new one has benefits compared to these two.

Basically, the distance of substitution positions (2.6Å) is similar to phenyl (2.9Å) and the linearity is almost no problem (φ＝176°). Addition of an oxygen atom reduced lipophilicity compared to bicyclo[2.2.2]octane. Also the stability issue of cubane structure is solved by scaffold hopping.

It is great to pay an intense effort to solving the issues of current bioisosteres and expand the chemical possibility of structure switching and scaffold hopping. But significant efforts have also been done for making ways to rational design of bioisosteres. Take for instance, MolOpt³⁾ and MB-Isoster⁴⁾ were developed for this purpose. MolOpt is a company-driven and MB-Isoster is an academia-derived web-based software to seek for potential bioisostares.

The detail of the algorism is described in each paper, but basically, the authors take advantage of database to search and furnished their own algorism to propose a list of analogous molecules with different structures. It is, of course, help medicinal chemists to design the next molecules to synthesize.

The games are changing and an interesting paper appeared in this field.⁵⁾ The paper aimed for isosteric replacement of ribose and its related sugars, which is prevalent in our signal molecules like DNA and RNA.

The author utilized data to figure out the scaffolds of bioisosteres but in the context of an ensemble of align- and structure-based approaches. There are so many selective interactions in our body bridged by ribose-like sugars. This data mining approach enabled rational design of glycosyl domain with a non-sugar scaffold.

Even though the effectiveness of the last approach has not been fully elucidated in a biological sense so far, in silico approaches of a selected and reasonable dataset are making ways to rational bioisostere prediction.

We are thinking this kind of approach accelerate expanding our PepMetics®. scaffolds. Our chemical space is expanding but we’d be glad if you are interested in more expansion with your idea or technology.

1) https://prismbiolab.com/bioisosteres-are-still-developing-examples-of-fascinating-phenyl-bioisosteres/
2) https://doi.org/10.1038/s41467-023-41298-3
3) http://dx.doi.org/10.2174/1573409915666190704093400
4) https://doi.org/10.1002/jcc.25581
5) https://doi.org/10.1021/acsomega.3c02243