Automated Molecular Design in BRADSHAW, Applied to the Optimization of ERAP1 Inhibitors
Generative design and machine learning are increasingly prevalent in medicinal chemistry. To pilot the comprehensive use of automated molecular design on a project, the BRADSHAW platform was used to optimize a series of inhibitors of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), an emerging target in cancer immunotherapy and autoimmune diseases. Through four consecutive iterations applying in silico molecular generation, property prediction and filtering, we conducted a multiparameter optimization of potency, physicochemical properties and pharmacokinetics. Continuous refinement of Machine Learning (ML) models led to improved scoring accuracy and compound quality, culminating in identification of in vitro and in vivo tool molecules. We also discuss our reflections on the pilot and integration of automated design into medicinal chemistry projects, including observations of the human factors resulting from increased use of computational design, and recommendations for future projects.
Authors
- Paul Scott‐Stevens
- Gail A. Seal
- Heather F. Hryczanek (ORCID: https://orcid.org/0000-0001-8972-8935)
- Semra Kitchen
- Robert P. Law (ORCID: https://orcid.org/0000-0002-2585-4585)
- Jared S. Marklew (ORCID: https://orcid.org/0000-0003-1389-2696)
- Richard Lonsdale (ORCID: https://orcid.org/0000-0001-9160-4659)
- J. S. Mason (ORCID: https://orcid.org/0000-0003-0062-2339)
- Péter Pogány (ORCID: https://orcid.org/0000-0003-3536-0746)
- Tim N. Barrett (ORCID: https://orcid.org/0000-0003-1005-0784)
- Callum J. Hall
- Christopher P. Tinworth (ORCID: https://orcid.org/0000-0002-2756-707X)
- David J. Hirst (ORCID: https://orcid.org/0000-0001-9969-2104)
- Rino A. Bit
- Efstratios Stratikos (ORCID: https://orcid.org/0000-0002-3566-2309)
- Darren V. S. Green (ORCID: https://orcid.org/0000-0001-9063-2754)
- Chloe L. Tayler (ORCID: https://orcid.org/0000-0002-5248-4145)
- Jonathan A. Taylor (ORCID: https://orcid.org/0000-0003-2381-6080)
- Simon Peace
- Ashley P. Hancock
- Matthew Gray
- Ian D. Wall
- Giovanni Vitulli (ORCID: https://orcid.org/0000-0003-0453-8513)
- Alex Phillipou
- Hester Sheehan (ORCID: https://orcid.org/0000-0002-2169-5206)
- Stephen D. Pickett (ORCID: https://orcid.org/0000-0002-0958-9830)
- James E. Rowedder
- Carl Haslam
- Jonathan P. Hutchinson
- Nicholas D. Measom (ORCID: https://orcid.org/0000-0001-5627-0366)
- David Marcus (ORCID: https://orcid.org/0000-0001-8932-4906)
- Margarete Neu
- Paul L Rowland
- Ross P. Hryczanek
- John J. Coward (ORCID: https://orcid.org/0009-0007-4174-0020)
Institutions
- National Centre of Scientific Research "Demokritos" (GR)
- GlaxoSmithKline (Croatia) (HR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-04-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03071
- Primary Topic
- Pharmacological Receptor Mechanisms and Effects
- Type
- article
- Field-Weighted Citation Impact
- 0.00