# QALPA: Property-guided diffusion modeling for efficient exploration of chemical spaces of flexible molecules

arXiv: https://arxiv.org/abs/2609.16527 · HTML: https://mlsanity.com/paper/2609.16527/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 15 of its 66 references that are in the map.
- First posted on arXiv 15 Sep 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 15 of 15)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Overcoming catastrophic forgetting in neural networks](https://mlsanity.com/paper/1612.00796/) (2016)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [MACE: Higher Order Equivariant Message Passing Neural Networks for Fast and Accurate Force Fields](https://mlsanity.com/paper/2206.07697/) (2022)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [Molecular De Novo Design through Deep Reinforcement Learning](https://mlsanity.com/paper/1704.07555/) (2017)
- [MiDi: Mixed Graph and 3D Denoising Diffusion for Molecule Generation](https://mlsanity.com/paper/2302.09048/) (2023)
- [Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2309.17296/) (2023)
- [Molecular Design in Synthetically Accessible Chemical Space via Deep Reinforcement Learning](https://mlsanity.com/paper/2004.14308/) (2020)
- [Computer-Aided Multi-Objective Optimization in Small Molecule Discovery](https://mlsanity.com/paper/2210.07209/) (2022)
- [PILOT: Equivariant diffusion for pocket conditioned de novo ligand generation with multi-objective guidance via importance sampling](https://mlsanity.com/paper/2405.14925/) (2024)

## Abstract (arXiv)

Exploring the chemical space of flexible molecules remains challenging because the vast number of possible compounds and conformations, together with the increasing cost and limited generalization of 3D generative models for larger and more complex molecules, restrict access to unexplored chemistry. Here, we introduce QALPA ("Quantum-Aware Learning for Property-space Augmentation"), a property-guided generative framework that combines an E(3)-equivariant diffusion model with active learning and efficient quantum-mechanical (QM) methods to iteratively explore targeted QM property manifolds. By coupling generation with physics-based evaluation, QALPA improves molecular sampling and model reliability in sparsely populated regions of chemical space. Our results show that training on complementary QM datasets spanning both small (QM7-X) and large (Aquamarine) drug-like compounds enables accurate molecular generation across a broad size range, improving transferability beyond the training distribution for complex property manifolds involving both extensive and intensive properties. As a proof of concept, QALPA coupled with the machine learning-augmented tight-binding method EquiDTB efficiently augments alloQM, a QM dataset introduced in this work, comprising 6,253 conformers of allosteric drug molecules, by populating sparse regions of the property landscape defined by the many-body dispersion energy and HOMO-LUMO energy gap. These results demonstrate that the integration of generative AI with efficient ML/QM methods offers a practical pathway toward augmenting sparse QM datasets and sustainably expanding the exploration of chemical space for molecular discovery.