Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design

Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the "Design" phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2024-08-12
DOI
https://doi.org/10.1021/acs.jmedchem.4c01034
Citations
9
Primary Topic
Computational Drug Discovery Methods
Type
article
Field-Weighted Citation Impact
3.25
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article

Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design

Haoran Tang, Erin L. Braybrooke, Adelphe M. Mfuh, Marianne Schimpl et al.
9 citations
Journal of Medicinal Chemistry
Computational Drug Discovery Methods
3.25
article

Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design

Haoran Tang, Erin L. Braybrooke, Adelphe M. Mfuh, Marianne Schimpl, Taylor R. Quinn, Alex J. Chinn, Caifeng Cui, Graeme R. Robb, Yukai Fan, Neil P. Grimster, Gayathri Bommakanti, Keishi Kohara, Gail L. Wrigley, Christina Chan, Samantha Jane Hughes, Huimin Zhu, Clare Thomson, Erin Code, Kevin J. Robbins, Michelle L. Lamb, Kathryn A. Giblin, Jeffrey A. Boerth, Yun Zhang, Lina Ma, Xue Lin, Jamie Ware
article en
9 citations

Abstract

Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the "Design" phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.

Journal of Medicinal ChemistryVol. 67(16)
AstraZeneca (United States) (US), AstraZeneca (Germany) (DE)
Good health and well-being
Openalex Percentile: Top 7%
Computational Drug Discovery Methods
3.25
DOIOpen Access PDFOpenAlex
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