# KinetiDiff: Docking-Guided Diffusion for De Novo ACVR1 Inhibitor Design in Fibrodysplasia Ossificans Progressiva

arXiv: https://arxiv.org/abs/2604.20886 · HTML: https://mlsanity.com/paper/2604.20886/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 7 of its 21 references that are in the map.
- First posted on arXiv 17 Apr 2026.

## Builds on (most cited first, 7 of 7)

- [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)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Generative Modeling by Estimating Gradients of the Data Distribution](https://mlsanity.com/paper/1907.05600/) (2019)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Geometry-Complete Diffusion for 3D Molecule Generation and Optimization](https://mlsanity.com/paper/2302.04313/) (2023)
- [General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design](https://mlsanity.com/paper/2406.16821/) (2024)

## Abstract (arXiv)

We present KinetiDiff, a structure-based framework for de novo kinase inhibitor design that integrates a Geometry-Complete Diffusion Model with real-time AutoDock Vina gradient guidance. By injecting physics-based docking gradients into the diffusion denoising loop, KinetiDiff steers molecule generation toward high-affinity conformations for ACVR1 (ALK2), the causative kinase in Fibrodysplasia Ossificans Progressiva. From 10,000 diffusion samples, the framework produced 9,997 valid molecules. The best candidate achieved -11.05 kcal/mol (pKd = 8.10), a 19.2% improvement over the crystallographic reference. The top 100 candidates all exceed the reference, with 100% Lipinski compliance, median synthetic accessibility of 2.67, and internal diversity of 0.790. Systematic ablation across four guidance strategies--Vina-Direct (physics), HNN-Denovo (neural proxy), multi-objective, and unguided--demonstrates that real-time docking guidance dominates on all metrics. We evaluate HNN-Denovo as a computationally efficient alternative (60-fold speedup per step), revealing a domain-mismatch limitation (r = 0.224 correlation with Vina) that explains its inferior performance. These results establish gradient-guided geometric diffusion as a practical approach for generating potent, synthetically accessible inhibitors against rare-disease kinase targets.