Improving hERG and Solubility for PROTACs

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Case Study 11

Improving hERG and Solubility for PROTACs

Generative modeling was adapted to design PROTAC structures and propose strategies to reduce hERG IC₅₀ while improving solubility across multiple PROTACs and a small molecule.

• PROTACs
• hERG
• Solubility
• Generative modeling
• Retrosynthesis

Challenge

The project aimed to propose strategies for reducing hERG IC₅₀ and improving solubility for multiple PROTAC molecules and one small molecule.

What We Did

1. 1
   Built hERG and solubility models

   Curated large datasets for both properties and used them to build machine-learning models.

2. 2
   Adapted MegaSyn for PROTAC generation

   Modified the MegaSyn generative approach to produce PROTAC structures using a database of known linkers.

3. 3
   Scored and assessed generated molecules

   Evaluated generated molecules with the hERG and solubility models, assessed drug-likeness, and applied our own retrosynthesis-scoring approach and similarity searches against SureChEMBL to assess freedom to operate.

What We Delivered

• Top-scoring molecules shared with the client.
• A full report on the modeling and molecule assessments.

Working to balance solubility and hERG liability in complex molecules?

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