Bioisosteric drug design is the replacement of an atom, functional group, or molecular fragment with another moiety selected to reproduce relevant steric, electronic, or interaction properties in a bioactive molecule. The replacement preserves selected features of molecular recognition while changing properties such as ionization, polarity, conformational preference, or susceptibility to metabolism. Bioisosteric relationships extend beyond atoms of similar valence and include replacements with substantially different chemical connectivity [1]. Saturated carbon frameworks can reproduce the spatial arrangement of substituents on an aromatic ring while changing three-dimensional shape and physicochemical behaviour [2]. For example, appropriately substituted bicyclo[3.1.1]heptanes can approximate the substituent vectors of meta-substituted benzene rings [3]. Functional group replacements can also preserve hydrogen bonding patterns; squaramides offer geometries and donor–acceptor features relevant to several amide-related groups [4]. Equivalence is therefore specific to the molecular setting and the property being preserved, rather than an assertion that two fragments have identical biological effects [1][2].
- bioisosteres
- molecular recognition
- scaffold replacement
- substituent geometry
References
- George A. Patani; Edmond J. LaVoie; Bioisosterism: A Rational Approach in Drug Design. Chem. Rev. 1996, 96, 3147-3176, 10.1021/cr950066q.
- Jet Tsien; Chao Hu; Rohan R. Merchant; Tian Qin; Three-dimensional saturated C(sp3)-rich bioisosteres for benzene. Nat. Rev. Chem. 2024, 8, 605-627, 10.1038/s41570-024-00623-0.
- Nils Frank; Jeremy Nugent; Bethany R. Shire; Helena D. Pickford; Patrick Rabe; Alistair J. Sterling; Tryfon Zarganes-Tzitzikas; Thomas Grimes; Amber L. Thompson; Russell C. Smith; et al. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 2022, 611, 721-726, 10.1038/s41586-022-05290-z.
- Kylie A. Agnew-Francis; Craig M. Williams; Squaramides as Bioisosteres in Contemporary Drug Design. Chem. Rev. 2020, 120, 11616-11650, 10.1021/acs.chemrev.0c00416.