# ShEPhERD: Diffusing shape, electrostatics, and pharmacophores for bioisosteric drug design

arXiv: https://arxiv.org/abs/2411.04130 · HTML: https://mlsanity.com/paper/2411.04130/

## Key facts

- Cited by 13 papers in the map (data through 14 Oct 2026).
- First posted on arXiv 22 Oct 2024.

## Built on by (most cited first, 13 of 13)

- [SynCoGen: Synthesizable 3D Molecule Generation via Joint Reaction and Coordinate Modeling](https://mlsanity.com/paper/2507.11818/) (2025)
- [Manipulating 3D Molecules in a Fixed-Dimensional E(3)-Equivariant Latent Space](https://mlsanity.com/paper/2506.00771/) (2025)
- [Joint Design of Protein Surface and Structure Using a Diffusion Bridge Model](https://mlsanity.com/paper/2511.16675/) (2025)
- [Latent Diffusion-Based 3D Molecular Recovery from Vibrational Spectra](https://mlsanity.com/paper/2603.06113/) (2026)
- [A Large-Scale Dataset and Benchmark: Do Protein-Ligand Models Learn Binding Sites or Just Binding Likelihood?](https://mlsanity.com/paper/2605.24045/) (2026)
- [JEDEL: Zero-Shot DNA-Encoded Library Design for Early-Stage Drug Discovery](https://mlsanity.com/paper/2606.23745/) (2026)
- [Sesame: Structure-Aware Molecular Generation via Spatial Density-Map Conditioning](https://mlsanity.com/paper/2606.23856/) (2026)
- [On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimization](https://mlsanity.com/paper/2607.02834/) (2026)
- [HEDGEHOG: Hierarchical Evaluation of Drug Generators Through Rigorous Filtration](https://mlsanity.com/paper/2607.13155/) (2026)
- [SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch](https://mlsanity.com/paper/2609.02963/) (2026)
- [Ensemble-Conditioned Molecular Design](https://mlsanity.com/paper/2609.15077/) (2026)
- [RIDE: Reference-Anchored Inference-Time Diffusion Editing for Scaffold Hopping](https://mlsanity.com/paper/2609.35623/) (2026)
- [OctMole: Multiscale 3D Molecular Generation with Hierarchical Spatial Flows](https://mlsanity.com/paper/2610.16586/) (2026)

## Abstract (arXiv)

Engineering molecules to exhibit precise 3D intermolecular interactions with their environment forms the basis of chemical design. In ligand-based drug design, bioisosteric analogues of known bioactive hits are often identified by virtually screening chemical libraries with shape, electrostatic, and pharmacophore similarity scoring functions. We instead hypothesize that a generative model which learns the joint distribution over 3D molecular structures and their interaction profiles may facilitate 3D interaction-aware chemical design. We specifically design ShEPhERD, an SE(3)-equivariant diffusion model which jointly diffuses/denoises 3D molecular graphs and representations of their shapes, electrostatic potential surfaces, and (directional) pharmacophores to/from Gaussian noise. Inspired by traditional ligand discovery, we compose 3D similarity scoring functions to assess ShEPhERD's ability to conditionally generate novel molecules with desired interaction profiles. We demonstrate ShEPhERD's potential for impact via exemplary drug design tasks including natural product ligand hopping, protein-blind bioactive hit diversification, and bioisosteric fragment merging.