# Target-aware Variational Auto-encoders for Ligand Generation with Multimodal Protein Representation Learning

arXiv: https://arxiv.org/abs/2309.16685 · HTML: https://mlsanity.com/paper/2309.16685/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 41 of its 74 references that are in the map.
- First posted on arXiv 2 Aug 2023.

## Builds on (most cited first, 30 of 41)

- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
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- [Rethinking Attention with Performers](https://mlsanity.com/paper/2009.14794/) (2020)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [Measuring and Relieving the Over-smoothing Problem for Graph Neural Networks from the Topological View](https://mlsanity.com/paper/1909.03211/) (2019)
- [Understanding over-squashing and bottlenecks on graphs via curvature](https://mlsanity.com/paper/2111.14522/) (2021)
- [Efficient Content-Based Sparse Attention with Routing Transformers](https://mlsanity.com/paper/2003.05997/) (2020)
- [MolGAN: An implicit generative model for small molecular graphs](https://mlsanity.com/paper/1805.11973/) (2018)
- [GraphVAE: Towards Generation of Small Graphs Using Variational Autoencoders](https://mlsanity.com/paper/1802.03480/) (2018)
- [Graph Convolutional Policy Network for Goal-Directed Molecular Graph Generation](https://mlsanity.com/paper/1806.02473/) (2018)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [Grammar Variational Autoencoder](https://mlsanity.com/paper/1703.01925/) (2017)
- [Cormorant: Covariant Molecular Neural Networks](https://mlsanity.com/paper/1906.04015/) (2019)
- [Long Range Graph Benchmark](https://mlsanity.com/paper/2206.08164/) (2022)
- [Hierarchical Generation of Molecular Graphs using Structural Motifs](https://mlsanity.com/paper/2002.03230/) (2020)
- [Optimization of Molecules via Deep Reinforcement Learning](https://mlsanity.com/paper/1810.08678/) (2018)
- [Fr'echet ChemNet Distance: A metric for generative models for molecules in drug discovery](https://mlsanity.com/paper/1803.09518/) (2018)
- [Pure Transformers are Powerful Graph Learners](https://mlsanity.com/paper/2207.02505/) (2022)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [GraphDF: A Discrete Flow Model for Molecular Graph Generation](https://mlsanity.com/paper/2102.01189/) (2021)
- [3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction](https://mlsanity.com/paper/2303.03543/) (2023)
- [DeepDTA: Deep Drug-Target Binding Affinity Prediction](https://mlsanity.com/paper/1801.10193/) (2018)
- [Pluralistic Image Completion](https://mlsanity.com/paper/1903.04227/) (2019)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [High-Fidelity Pluralistic Image Completion with Transformers](https://mlsanity.com/paper/2103.14031/) (2021)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [Syntax-Directed Variational Autoencoder for Structured Data](https://mlsanity.com/paper/1802.08786/) (2018)

## Abstract (arXiv)

Without knowledge of specific pockets, generating ligands based on the global structure of a protein target plays a crucial role in drug discovery as it helps reduce the search space for potential drug-like candidates in the pipeline. However, contemporary methods require optimizing tailored networks for each protein, which is arduous and costly. To address this issue, we introduce TargetVAE, a target-aware variational auto-encoder that generates ligands with high binding affinities to arbitrary protein targets, guided by a novel multimodal deep neural network built based on graph Transformers as the prior for the generative model. This is the first effort to unify different representations of proteins (e.g., sequence of amino-acids, 3D structure) into a single model that we name as Protein Multimodal Network (PMN). Our multimodal architecture learns from the entire protein structures and is able to capture their sequential, topological and geometrical information. We showcase the superiority of our approach by conducting extensive experiments and evaluations, including the assessment of generative model quality, ligand generation for unseen targets, docking score computation, and binding affinity prediction. Empirical results demonstrate the promising performance of our proposed approach. Our software package is publicly available at https://github.com/HySonLab/Ligand_Generation