MacroGuide: Topological Guidance for Macrocycle Generation
2026-02-16 • Machine Learning
Machine Learning
AI summaryⓘ
The authors created MacroGuide, a new method to help AI models generate ring-shaped molecules called macrocycles, which are important for drug discovery. They used a math tool called Persistent Homology to guide the AI in forming these rings, making the process much more effective. Their approach improved the rate of creating macrocycles from 1% to 99% and maintained high quality in the molecules produced. This method works both when generating molecules freely and when designing them to fit specific protein targets.
MacrocyclesGenerative modelsDiffusion modelsPersistent HomologyVietoris-Rips complexMolecular generationTopological constraintsProtein pocketChemical validityPoseBusters
Authors
Alicja Maksymiuk, Alexandre Duplessis, Michael Bronstein, Alexander Tong, Fernanda Duarte, İsmail İlkan Ceylan
Abstract
Macrocycles are ring-shaped molecules that offer a promising alternative to small-molecule drugs due to their enhanced selectivity and binding affinity against difficult targets. Despite their chemical value, they remain underexplored in generative modeling, likely owing to their scarcity in public datasets and the challenges of enforcing topological constraints in standard deep generative models. We introduce MacroGuide: Topological Guidance for Macrocycle Generation, a diffusion guidance mechanism that uses Persistent Homology to steer the sampling of pretrained molecular generative models toward the generation of macrocycles, in both unconditional and conditional (protein pocket) settings. At each denoising step, MacroGuide constructs a Vietoris-Rips complex from atomic positions and promotes ring formation by optimizing persistent homology features. Empirically, applying MacroGuide to pretrained diffusion models increases macrocycle generation rates from 1% to 99%, while matching or exceeding state-of-the-art performance on key quality metrics such as chemical validity, diversity, and PoseBusters checks.