On the Art of Compiling and Using 'Drug‐Like' Chemical Fragment Spaces

Abstract

Ever since the first rational approaches to the discovery of promising lead candidate structures were applied, it has been a challenge for both medicinal and computational chemists to assess, generate, and combine promising structural motifs to form new and potent chemical entities for biological screening against potential drug targets. Many scientists have committed themselves to the analysis and identification of valuable chemical building blocks and have also developed strategies on how to best recombine them. In this context, the retrosynthetic fragmentation and recombination of chemical motifs derived from known inhibitors is a common and well-known procedure. Meanwhile, fragment-based approaches have become established and valuable processes in pharmaceutical lead discovery and validation. Several application studies have yielded promising lead candidates. [2] Chemical space is huge. Corporate as well as public databases are in the millions and are still increasing in size in order to cover a larger part of the chemical universe. For several good reasons, there is the common trend to standardize experimental and computational protocols in pharmaceutical research. This trend demands systematic and consistent approaches, although they can hardly match the creativity and intuition of medicinal chemists. Consequently, they can and should not substitute, but rather assist, the expert in this task. The most prominent automated example for fragment generation is the retrosynthetic combinatorial analysis procedure (RECAP).[3] It was the first of its kind to apply 11 distinct rules that were supposed to model chemical motifs that could easily be formed by combinatorial chemistry. In this context, the "fragment space" concept was introduced. In contrast to a fragment library, such a space consists not only of a set of fragments, but also of a set of rules that specifies how to recombine fragments by fusing the respective chemical motifs.RECAP is widely used and often referred to, yet even though authors frequently state to have used modified improved versions of the original, actual publications that communicate the extensions that were carried out are rare. An extension of the fragment space concept was recently published, but with a focus on obtaining scaffolds and not on retaining supposedly 'drug-like' substituents or functional groups.[4] Apart from that, the question remains what a 'drug-like' fragment space actually is, and whether or not 'drug-likeness' depends on the origin of the fragments: that is, if they necessarily have to be derived from drugs. In this context, it is highly interesting and important to measure the extent and accuracy with which current models and methods are able to represent the available chemical space.In an attempt to improve existing approaches for the automatic decomposition of molecules into fragments, we compiled a new and more elaborate set of rules for the breaking of retrosynthetically interesting chemical substructures (BRICS) and used this for obtaining fragments from biol...

Computational Methods in Drug Discovery

“…The linker plays the role of varying the distances between the scaffold and functional groups. RECAP (Retrosynthetic Combinatorial Analysis Procedure) was the first fragment generation method to incorporate rules that limit the chemical reactions to ones used in typical combinatorial chemistry techniques, thereby limiting the possible fragments as well as possible recombination patterns (Lewell et al, 1998;Degen et al, 2008).…”

Second-generation de novo design: a view from a medicinal chemist perspective

“…We used a selection of CDK2, CHEK1, JNK3, PDE4b, PDE5a, BACE, ROCK1, and ESR1 protein complexes. Fragment spaces from ligands of the same protein class were generated using conversion to mol2 format with CORINA [12,13] and shredding with CoLibri/Recore [14] with the help of the BRICS rule set [15]. Figure 1 shows the workflow of the studies performed.…”

De novo design by pharmacophore-based searches in fragment spaces

“…The BRICS fragment space For the following results, the BRICS cleavage rules and fragment spaces [6] were used. The cleavage rules are a modified superset of the RECAP rules.…”

“…Structural motifs which are undesired can be excluded, while motifs which represent common building blocks of drugs can be included. Furthermore, there is evidence that the resulting molecules are more drug-like, if the fragments have been obtained by cleaving drug molecules [5][6][7]. By encoding standard synthetic reactions in the connection rules, the generated molecules may also be easier to synthesize [8].…”