Enabling late-stage drug diversification by high-throughput experimentation with geometric deep learning

2022/11/15 by David F. Nippa, Kenneth Atz, Remo Hohler +13 · 1 voice
Biochemistry, Genetics and Molecular Biology · Computer Science · Materials Science · #Chemical Synthesis and Analysis #Computational Drug Discovery Methods #Machine Learning in Materials Science

paper · pdf · doi:10.26434/chemrxiv-2022-gkxm6-v2

openalex publication_date 2022/11/15 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/14

Abstract

Late-stage functionalization (LSF) is an economical approach to optimize the properties of drug candidates. However, the chemical complexity of drug molecules often makes late-stage diversification challenging. To address this problem, an LSF platform based on geometric deep learning and high-throughput reaction screening was developed. Considering borylation as a critical step in LSF, the computational model predicted reaction yields for diverse reaction conditions with a mean absolute error margin of 4–5%, while the reactivity of novel reactions with known and unknown substrates were classified with a balanced accuracy of 92% and 67%, respectively. The regioselectivity of the major products was accurately captured in up to 90% of the cases studied. When applied to 23 diverse commercial drug molecules, the platform successfully identified numerous opportunities for structural diversification. The influence of steric and quantum mechanical information on model performance was quantified and a new comprehensive simple user-friendly reaction format (SURF) is introduced which proved to be a key enabler for seamlessly integrating deep learning and high-throughput experimentation (HTE) for LSF.

Citations

• The FAIR Guiding Principles for scientific data management and stewardship
• Predicting Organic Reaction Outcomes with Weisfeiler-Lehman Network
• PyTorch: An Imperative Style, High-Performance Deep Learning Library
• The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time
• Accurate Learning of Graph Representations with Graph Multiset Pooling
• Learning Graph Models for Retrosynthesis Prediction
• Late-stage C–H functionalization offers new opportunities in drug discovery
• Advances in Neural Information Processing Systems 32 (NeurIPS 2019)

Discussions

• It was a key technology to connect our semi-automated high-throughput late-stage functionalization platform to machine learning algorithms which we have pursued in these preprints: doi.org/10.26434/ch [bsky, 0 points, 1 comments]