Bioisosteres

Bioisosteres are chemical substituents or groups with similar physical or chemical properties that produce broadly similar biological effects when substituted within a compound. The concept of bioisosterism is used to modify the biological properties of a compound while retaining the desired activity. The primary goal is to enhance the pharmacokinetic and pharmacodynamic properties of a molecule, such as its bioavailability, metabolic stability, potency, and selectivity.

Importance in Computational Drug Discovery:

• Improved Drug Properties: Bioisosteric replacements can enhance the drug-like properties of a molecule, such as solubility, permeability, and stability, without significantly altering its biological activity.
• Reduced Toxicity: Substituting toxic groups with bioisosteres can reduce the toxicity of a compound, making it safer for therapeutic use.
• Patentability: Bioisosteric modifications can lead to novel compounds that may be patentable, providing intellectual property protection.
• Overcoming Resistance: In cases where drug resistance is an issue, bioisosteres can be used to develop new analogs that retain activity against resistant strains or targets.
• Structure-Activity Relationship (SAR) Studies: Bioisosteres help in understanding the SAR by systematically altering parts of the molecule and studying the effects on biological activity.

Key Tools

• Scaffold Hopping Tools:

• Tools like Schrödinger’s Phase and OpenEye’s ROCS help in identifying bioisosteres and performing scaffold hopping to generate new chemical entities.

• Bioisostere Databases:

• Databases like the BIOSTER database provide a comprehensive collection of bioisosteric replacements used in medicinal chemistry.

• Computational Chemistry Software:

• Software like RDKit and MOE (Molecular Operating Environment) include functionalities for identifying and evaluating bioisosteric replacements.

• DeepOrigin Tools:

• QED: For evaluating the drug-likeness of molecules, useful in assessing bioisosteric replacements.

• LogP, LogS, LogD: For predicting molecular properties like solubility and partition coefficients after bioisosteric modifications.

• The above and additional tools are available via Balto and API.

Literature

• Bioisosteres in drug discovery: focus on tetrazole

• Publication Date: 2019-11-25

• DOI: 10.4155/fmc-2019-0288

• Summary: This paper focuses on the application of tetrazoles as bioisosteres in drug discovery, discussing their properties and use cases.

• Investigating 3,3-Diaryloxetanes as Potential Bioisosteres in Drug Discovery

• Publication Date: 2021-04-21

• DOI: 10.26434/CHEMRXIV.14453187.V1

• Summary: This study explores the properties of 3,3-diaryloxetanes as bioisosteres and their potential as replacements in drug-like compounds, demonstrating superior properties compared to related alkyl linkers.

• Physicochemical and Biological Evaluation of gem-Difluorinated Saturated Oxygen Heterocycles as Bioisosteres for Drug Discovery

• Publication Date: 2024-12-11

• DOI: 10.1002/chem.202404390

• Summary: Evaluates gem-difluorinated O-heterocyclic substituents as bioisosteres, demonstrating their utility in MAPK kinase inhibitors.

• The application of bioisosteres in drug design for novel drug discovery: focusing on acid protease inhibitors

• Publication Date: 2012-09-25

• DOI: 10.1517/17460441.2012.712513

• Summary: Discusses the application of bioisosteres in drug design, particularly for renin, HIV-protease, and β-secretase inhibitors, and proposes new terms ‘electron-donor bioisostere’ and ‘conformational bioisostere’.

• “Angular” Spirocyclic Azetidines: Synthesis, Characterization, and Evaluation in Drug Discovery

• Publication Date: 2024-12-02

• DOI: 10.1002/anie.202418850

• Summary: Synthesizes and validates “angular” spirocyclic azetidines as bioisosteres for common saturated six-membered heterocycles in drug discovery.

• Tetraasteranes as homologues of cubanes: effective scaffolds for drug discovery

• Publication Date: 2024-09-12

• DOI: 10.1039/d4ob01043d

• Summary: Evaluates tetraasteranes as novel bioisosteres of cubanes, showing enhanced affinity and stability in drug discovery applications.

• Omega-3 polyunsaturated fatty acid derived lipid mediators: a comprehensive update on their application in anti-cancer drug discovery

• Publication Date: 2024-04-09

• DOI: 10.1080/17460441.2024.2340493

• Summary: Reviews the application of ω-3 PUFA-derived lipid mediators in anticancer drug discovery, highlighting bioisosteric modifications.

• Selective P450BM3 Hydroxylation of Cyclobutylamine and Bicyclo[1.1.1]pentylamine Derivatives: Underpinning Synthetic Chemistry for Drug Discovery

• Publication Date: 2023-12-05

• DOI: 10.1021/jacs.3c10542

• Summary: Demonstrates the selective hydroxylation of cyclobutylamine derivatives, providing a route to chiral BCP bioisosteres for medicinal chemistry.

• Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery

• Publication Date: 2022-10-07

• DOI: 10.1021/acs.jmedchem.2c00969

• Summary: Highlights the use of scaffold hopping and bioisosteric replacements in CNS drug discovery, emphasizing refined terminology.

• Phenyl bioisosteres in medicinal chemistry: discovery of novel γ-secretase modulators as a potential treatment for Alzheimer’s disease

• Publication Date: 2021-04-12

• DOI: 10.1039/D1MD00043H

• Summary: Proposes the use of bridged piperidine as a phenyl bioisostere, leading to improved drug-like properties.