The Heterocycle Isostere Explorer: A Computational Tool for the Discovery of Novel Aromatic Heterocyclic Isosteres

Holland, MTO ORCID: 0000-0003-2322-4384, Sebastián-Pérez, V ORCID: 0000-0002-8248-4496, Bradley, AR ORCID: 0000-0002-0881-3490, Duarte, F ORCID: 0000-0002-6062-8209 and Brennan, PE (2026) The Heterocycle Isostere Explorer: A Computational Tool for the Discovery of Novel Aromatic Heterocyclic Isosteres Journal of Medicinal Chemistry, 69 (4). pp. 4408-4423. ISSN 0022-2623, 1520-4804

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Abstract

Aromatic heterocycles are central to many areas of chemistry and play an important role in medicinal chemistry, where they are frequently used as bioisosteres to modulate molecular properties while preserving potency. Here, we report the heterocycle isostere explorer (HCIE), an easy-to-use, open-source Python tool for identifying heterocyclic bioisosteres from a custom-built virtual library of over 500,000 optionally functionalized aromatic heterocycles. HCIE employs a unique vector-based alignment and ranks candidates using the combined shape and electrostatic similarity. We describe its use in a series of medicinal chemistry case studies and propose novel 5,5-bicyclic molecules as bioisosteres of 2-pyridine, a common motif in FDA-approved drugs. By integrating 3D similarity metrics with physicochemical descriptors, HCIE provides medicinal chemists with a practical and extensible framework for early stage compound design while highlighting underexplored heterocycles whose predicted utility may motivate the development of new synthetic methodologies.

Item Type:	Article
Uncontrolled Keywords:	Heterocyclic Compounds, Pyridines, Software, Drug Discovery, Bioisosterism
Divisions:	Faculty of Science & Engineering Faculty of Science & Engineering > School of Physical Sciences Faculty of Science & Engineering > School of Physical Sciences > Chemistry
Depositing User:	Symplectic Admin
Date Deposited:	21 May 2026 08:43
Last Modified:	13 Jun 2026 02:00
DOI:	10.1021/acs.jmedchem.5c03118
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3198574
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