Bioisosteric fragment

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. 

Here we briefly review the publications that have used the Bioster database as a source of bioisosteric fragments for the evaluation of bioisosteric (dis) similarity. 

A set of 185 small functional groups and rings extracted from Bioster 98.1 database was a validation tool for a similarity calculation method of bioisosteric fragment pairs in the IsoStar library, which is derived from crystallographic and theoretical data for some 250 chemical groupings [57]. 

Sets of substituent pairs of 418 bioisosteric fragments from Bioster 98.1 were used for the validation of the newly defined R-group descriptors, characterizing the physicochemical properties of ring substituents, to (dis)similarity estimation [58]. 

Kennewell, E.A., Wdlett, P., Ducrot, P., and Luttmann, C. (2006) Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data. Journal of Computer-Aided Molecular Design, 20, 385-394. 

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. 

To correctly address the problem of identification of target-specific privileged motifs, one should take into account the phenomenon of bioisosterism [26]. Thus, several different bioisosteric structures can constitute only one distinct privileged structural motif. In order to include all possible bioisosteric analogs into one cluster, we use a special algorithm of ChemoSoft based on a collection of rules for bioisosteric conversions described in literature. AH bioisosteric analogs are considered similar with similarity coefficient 1 if they have identical substituents around the central bioisosterically transformed fragment. 

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.

Peptide-like compounds raise the further significant issue of chirality control. When all the chiral fragments consist of natural amino acids, the chiral sources are natural amino acids themselves. However, when chiral non-natural amino acids are used as bioisosteres of amino acid residues to construct peptide mimetic compounds, the chirality needs to be constructed as efficiently as possible. Multi-step or low-yielding processes resulting from the necessity to control chirality often lead to the potential risk of large amounts of waste and a high environmental burden. 

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.

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