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#1 Scalable and Cost-Efficient de Novo Template-Based Molecular Generation [PDF] [Copy] [Kimi] [REL]

Authors: Piotr Gaiński, Oussama Boussif, Andrei Rekesh, Dmytro Shevchuk, Ali Parviz, Mike Tyers, Robert A. Batey, Michał Koziarski

Template-based molecular generation offers a promising avenue for drug design by ensuring generated compounds are synthetically accessible through predefined reaction templates and building blocks. In this work, we tackle three core challenges in template-based GFlowNets: (1) minimizing synthesis cost, (2) scaling to large building block libraries, and (3) effectively utilizing small fragment sets. We propose **Recursive Cost Guidance**, a backward policy framework that employs auxiliary machine learning models to approximate synthesis cost and viability. This guidance steers generation toward low-cost synthesis pathways, significantly enhancing cost-efficiency, molecular diversity, and quality, especially when paired with an **Exploitation Penalty** that balances the trade-off between exploration and exploitation. To enhance performance in smaller building block libraries, we develop a **Dynamic Library** mechanism that reuses intermediate high-reward states to construct full synthesis trees. Our approach establishes state-of-the-art results in template-based molecular generation.

Subject: NeurIPS.2025 - Poster