Bioisosteric fragment replacement

The applicability of such VS in combination with tools available include situations where portions of any molecule need replacement with bioisosteric fragments. In this regard, BROOD software [105] and MOE [222] provide automated tools for fragment removal, replacement, and minimization to relieve any strain in the molecular assembly step and provide a database of fragments(isosteres) that could be enhanced in custom fashion by an enterprise as well. These software allow facile FBVS in 3D. Since this software has become available within the last 2 years, there seem to be a dearth of use cases in the published literature. However, anecdotal reports indicate that these are being used regularly in industry and the Websites of these two vendors provide adequate information for the inquisitive reader. 

Rescaffolding, bioisosteric replacement, or fragment replacement all describe workflows where a part of a molecule is replaced by another chemical moiety by retaining the biological activity [13]. The aim of this process is the design of molecules with novel IP or different properties. This concept has a long history in medicinal chemistry, but recently this process is heavily supported by methods of computational chemistry. Based on the retrospective evaluation of COX inhibitors, we will discuss this approach in more detail. 

Further development in the chemistry of oxazolidinone antibacterials was based mainly on the assumption that the 4-pyridyl moiety of one of Dupont s lead compounds, E-3709, might be amenable to replacement by suitably saturated heterocyclic bioisosteres [48]. This assumption was based on an example in which successful replacement of the piperazine ring system in the quinolone antibacterials, such as ciprofloxacin, with a pyridine fragment, such as seen in Win-57273, results in improvement of both the antibacterial and the pharmacokinetic profiles of the compounds. Similarly, as in the case of ciprofloxacin and Win-57273, it was predicted that the presence of a small but highly electron-withdrawing fluorine atom would be tolerated at the meta position(s) of the central phenyl ring, and would confer enhanced antibacterial activity and/or other desirable properties to the targeted oxazolidinones, as shown in Fig. 3. 

Figure 1.5 Bioisosteres. These are biologically equivalent molecular fragments that can be used to replace portions of a drug molecule.

Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified in Step B, a process such as an alanine scan is used to identify which of the amino acids are important for bioactivity in Step C, individual amino acids have their configuration changed from the naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make the peptide less naturally peptidic ) in Step D, individual amino acids are replaced with atypical unnatural amino acids and amino acid mimics in Step E the peptide is cychzed to constrain it con-formationally finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in an attempt to make a non-peptidic organic molecule.

Figure 7.12 show the results of a validation study. The task was to identify bioisosteric replacements for fragments in known PPAR (peroxisome pro-liferator-activated receptor) ligands. Fibrates are therapeutic agents for the treatment of metabolic disorders and activate PPARoc, a member of the PPAR family.It has been demonstrated that the 2-methyl-propionic acid moiety 7.6 is responsible for the selectivity of fibrates toward PPARa. SQUIRRELnovo suggests bioisosteric replacement for this group. These groups have been patented for action on PPARoc. ... 

Figure 7.12 Bioisosteric replacement of 2-methylpropionic acid in 7.6. These fragments were suggested by SQUIRRELnovo based on shape matching (mesh) and pharmacophore point scoring (LIQUID fuzzy pharmacophore method). All bioisosteres have been proven to exhibit the desired bioactivity as building-blocks for PPAR agonists.

This section describes the application of Bioster database to medicinal chemistry problems. In the first example, the database was helpful in finding replacements for the pharmacologically unfavorable benzodioxole ring. Next, an earlier analysis is updated by tabulated examples of phenol bioisosteres. Finally, selected examples from a fragment query for a-ketoamide bioisosteres are presented. 

In order to calculate the similarity between fragments (substituents, spacers, or rings) that one wants to replace in the process of bioisosteric design, it is necessary to quantify somehow their properties and express them as a set of numerical values -descriptors. In the classical years of quantitative structure-activity relationship (QSAR), the properties of substituents were mostly characterized by experimentally derived parameters. Hammett sigma constants a (and several variations of this parameter) played a prominent role in characterizing the electron-donating or electron-accepting power of substituents 7], and the Hansch n parameter, defined... 

Lewell et al. proposed the application of the RECAP rules to provide automated sets of monomers to be applied in designing combinatorial libraries. Fragments were grouped according to the biological activity for which they had an indication, which can be seen as a rudimentary approach to bioisosteric replacement (Figure 8.3). 

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