# RIDE: Reference-Anchored Inference-Time Diffusion Editing for Scaffold Hopping

arXiv: https://arxiv.org/abs/2609.35623 · HTML: https://mlsanity.com/paper/2609.35623/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 27 of its 42 references that are in the map.
- First posted on arXiv 28 Sep 2026.

## Builds on (most cited first, 27 of 27)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Prompt-to-Prompt Image Editing with Cross Attention Control](https://mlsanity.com/paper/2208.01626/) (2022)
- [Diffusion Posterior Sampling for General Noisy Inverse Problems](https://mlsanity.com/paper/2209.14687/) (2022)
- [Null-text Inversion for Editing Real Images using Guided Diffusion Models](https://mlsanity.com/paper/2211.09794/) (2022)
- [DiffusionCLIP: Text-Guided Diffusion Models for Robust Image Manipulation](https://mlsanity.com/paper/2110.02711/) (2021)
- [Argmax Flows and Multinomial Diffusion: Learning Categorical Distributions](https://mlsanity.com/paper/2102.05379/) (2021)
- [EDICT: Exact Diffusion Inversion via Coupled Transformations](https://mlsanity.com/paper/2211.12446/) (2022)
- [An Edit Friendly DDPM Noise Space: Inversion and Manipulations](https://mlsanity.com/paper/2304.06140/) (2023)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction](https://mlsanity.com/paper/2303.03543/) (2023)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [Derivative-Free Guidance in Continuous and Discrete Diffusion Models with Soft Value-Based Decoding](https://mlsanity.com/paper/2408.08252/) (2024)
- [Test-time Alignment of Diffusion Models without Reward Over-optimization](https://mlsanity.com/paper/2501.05803/) (2025)
- [DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design](https://mlsanity.com/paper/2403.07902/) (2024)
- [Inference-Time Alignment in Diffusion Models with Reward-Guided Generation: Tutorial and Review](https://mlsanity.com/paper/2501.09685/) (2025)
- [Inference-Time Alignment of Diffusion Models with Direct Noise Optimization](https://mlsanity.com/paper/2405.18881/) (2024)
- [Diffusion Tree Sampling: Scalable inference-time alignment of diffusion models](https://mlsanity.com/paper/2506.20701/) (2025)
- [Aligning Target-Aware Molecule Diffusion Models with Exact Energy Optimization](https://mlsanity.com/paper/2407.01648/) (2024)
- [Training-Free Guidance Beyond Differentiability: Scalable Path Steering with Tree Search in Diffusion and Flow Models](https://mlsanity.com/paper/2502.11420/) (2025)
- [ShEPhERD: Diffusing shape, electrostatics, and pharmacophores for bioisosteric drug design](https://mlsanity.com/paper/2411.04130/) (2024)
- [Generating 3D Binding Molecules Using Shape-Conditioned Diffusion Models with Guidance](https://mlsanity.com/paper/2502.06027/) (2025)
- [Fast Direct: Query-Efficient Online Black-box Guidance for Diffusion-model Target Generation](https://mlsanity.com/paper/2502.01692/) (2025)
- [Chemistry-Inspired Diffusion with Non-Differentiable Guidance](https://mlsanity.com/paper/2410.06502/) (2024)
- [Lookahead Sample Reward Guidance for Test-Time Scaling of Diffusion Models](https://mlsanity.com/paper/2602.03211/) (2026)
- [TurboHopp: Accelerated Molecule Scaffold Hopping with Consistency Models](https://mlsanity.com/paper/2410.20660/) (2024)
- [Generating Developable 3D Molecules via Pocket-Conditioned Diffusion and Property-Aware Optimization](https://mlsanity.com/paper/2607.12349/) (2026)

## Abstract (arXiv)

Scaffold hopping is a critical task in drug discovery, which seeks to discover new, structurally distinct molecules that share key functional groups and similar 3D shape with a reference binding ligand. Existing diffusion-based scaffold hopping methods formulate the problem as conditional generation of scaffolds given the functional groups. However, they lack a principled mechanism to jointly enforce 2D structural novelty and preserve the 3D shape of the reference ligand. Here, we introduce RIDE, a Reference-anchored Inference-time Diffusion Editing framework for scaffold hopping. RIDE recovers the reference diffusion noise trajectory conditioned on the binding pocket and functional groups, selects an optimal trajectory segment for editing via noise perturbation, and conducts a value-guided scaffold sampling to generate new scaffolds. Extensive experimental results demonstrate that, compared to baselines, RIDE consistently generates scaffolds with lower 2D similarity and higher 3D similarity to the reference, with an average improvements of 11.7% and 7.3%, respectively. Further analysis reveals that RIDE can accommodate various reward functions, and can preserve 3D similarity even when this is not explicitly included in the reward. Two case studies illustrate RIDE's ability to generate distinct scaffolds with different structures and properties, and its ability to introduce substantial 2D variation while maintaining very high 3D similarity. RIDE is publicly available at https://anonymous.4open.science/r/RIDE-C8A0.