Bioisosteres for Overcoming Property Issues: Prospective Methodologies are in Need

Switching a problematic functional group to a surrogate bioisostere is a powerful strategy for pharmacophore-based lead generation and optimization. Carboxylic acids,¹⁾,²⁾ peptide bonds,³⁾ amines as well as aromatic rings including phenols and indoles often displays crucial role as the constituents of pharmacophores. However, a severe struggle would arise when the key functional group possesses undesirable chemical and/or molecular properties. Isosteric replacement exerts a vital role as a strategical improvement of the molecular nature.

Cell permeability is often an accompanying problem in peptide drug field to bring forth an orally bioavailable drug. The polar nature of peptides due to the presence of peptide bonds, carboxylic acids, primary amines, guanidines and so on.

Characterization and analysis of various structures is necessary in order to rationally pick up a probable bioisostere, Structure property relationship analysis and experimentally evaluative methodologies serve as tools for the better selection of the key surrogate discovery.

Here are the series of articles that analyzed carboxylic acid isosteres.⁴⁾,⁵⁾,⁶⁾ Structure property relationship was analyzed through the systematical calculated and experimentally measured the parameters below.

- Aqueous solubility (pH 7.4, experimental)
- LogD7.4 (pH 7.4, experimental and calculated)
- PAMPA (experimental, Pe, %retention, logPapp)
- pKa (experimental and calculated)
- %fu (plasma protein binding, PPB, experimental)

Their analysis indicated that LogD7.4 (lipophilicity), pKa (acidity) and LogPapp (apparent permeability) showed statistically meaningful correlation for various carboxylic acids and sulfonamides. In the case of fluorinated carboxylic acid surrogates, the correlation of the three parameters had a slight difference from the others.
Fluorinated alcohols and phenols showed the similarity in terms of the correlation between lipophilicity and permeability, but the acidity was lower than the other two. It demonstrated the acidity could be controllable separately from lipophilicity and permeability by the use of fluorine’s unique nature.

Here is another report on the effect of bioisosterism analyzed by the EPSA (experimental polar surface area)⁷⁾,⁸⁾ instead of calculated PSA.⁹⁾,¹⁰⁾ EPSA is an empirical parameter measurable by SFC and it tells the polarity of the overall molecular entity including conformation and hydrogen bonding. EPSA prediction from the molecular structure is also possible in order for the comparison purpose in a prospective manner.¹¹⁾,¹²⁾

This study utilized the framework of MMPs (matched molecular pairs) to assess the property effects of bioisosteres. The authors standardized the workflow for the identification of MMPs to run the survey systematically. Changes in EPSA (ΔEPSA) by switching peptide bonds, carboxylic acids, and phenols to their well-known bioisosteres were evaluated by their workflow. In most cases, a trend is observed according to the structure of bioisostere of interest.
For example, bioisomerism of an amide to the N-Me amide lowers the EPSA in the order of ~10. A switch of the carbonyl group of an amide to an oxetane has a subtle effect on ΔEPSA.
A carboxyl group to a nitro group showed negative shift of the EPSA to a variety of extents. The similar trend is observed for the replacement of phenol to the pyridine. ΔEPSA is mostly negative but positive shift is also found in some cases.
EPSA-based evaluation is now possible in both retrospective and prospective ways. It is necessary to confirm the predictability of the bioisomeric switch effect according to the structure pair, but this research showed that ΔEPSA is a worthwhile parameter to take a look in drug design.

Bioisosteres are useful tools for the improvement of molecular properties, but it is not efficient to synthesize all the potential compounds with known or designed bioisosteres. It is desirable to identify the optimal MMP with a minimal effort of synthesis. Prospective approach for the prediction of molecular nature is crucial and there has been a huge demand of novel technologies.

In the field of peptide drug discovery, a switch from the peptide structure to the corresponding peptidomimetics is another way to obtain a molecule with the desirable molecular property. PepMetics®. molecules is playing a pivotal role for this purpose now.
If you have a bit of interest in scaffold switch from a peptide to a small molecule, we could make a contribution. Please contact us and have a discussion with us to see the possibility for giving birth to a drug candidate.

1) https://doi.org/10.1016/j.bmc.2024.117653
2) https://doi.org/10.2174/0929867328666210820112126
3) https://doi.org/10.1021/acs.jmedchem.0c00530
4) https://doi.org/10.1021/acs.jmedchem.5b01963
5) https://doi.org/10.1016/j.ejmech.2021.113399
6) https://doi.org/10.1016/j.bmcl.2023.129363
7) https://doi.org/10.1021%2Facsmedchemlett.2c00114
8) https://pubmed.ncbi.nlm.nih.gov/25313332/
9) https://doi.org/10.1023%2FA%3A1012188625088
10) https://doi.org/10.1023%2FA%3A1015040217741
11) https://doi.org/10.5599%2Fadmet.529
12) https://doi.org/10.1021%2Facs.molpharmaceut.6b00724