# Structure-Based Drug Design via 3D Molecular Generative Pre-training and Sampling

arXiv: https://arxiv.org/abs/2402.14315 · HTML: https://mlsanity.com/paper/2402.14315/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 28 of its 55 references that are in the map.
- First posted on arXiv 22 Feb 2024.

## Builds on (most cited first, 28 of 28)

- [Trust Region Policy Optimization](https://mlsanity.com/paper/1502.05477/) (2015)
- [Asynchronous Methods for Deep Reinforcement Learning](https://mlsanity.com/paper/1602.01783/) (2016)
- [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)
- [MolGAN: An implicit generative model for small molecular graphs](https://mlsanity.com/paper/1805.11973/) (2018)
- [Graph Convolutional Policy Network for Goal-Directed Molecular Graph Generation](https://mlsanity.com/paper/1806.02473/) (2018)
- [GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation](https://mlsanity.com/paper/2001.09382/) (2020)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Optimization of Molecules via Deep Reinforcement Learning](https://mlsanity.com/paper/1810.08678/) (2018)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [Learning Gradient Fields for Molecular Conformation Generation](https://mlsanity.com/paper/2105.03902/) (2021)
- [Deep Reinforcement Learning for De-Novo Drug Design](https://mlsanity.com/paper/1711.10907/) (2017)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [MARS: Markov Molecular Sampling for Multi-objective Drug Discovery](https://mlsanity.com/paper/2103.10432/) (2021)
- [GeoMol: Torsional Geometric Generation of Molecular 3D Conformer Ensembles](https://mlsanity.com/paper/2106.07802/) (2021)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [Molecular geometry prediction using a deep generative graph neural network](https://mlsanity.com/paper/1904.00314/) (2019)
- [Learning Neural Generative Dynamics for Molecular Conformation Generation](https://mlsanity.com/paper/2102.10240/) (2021)
- [MolecularRNN: Generating realistic molecular graphs with optimized properties](https://mlsanity.com/paper/1905.13372/) (2019)
- [A Generative Model for Molecular Distance Geometry](https://mlsanity.com/paper/1909.11459/) (2019)
- [Augmenting Genetic Algorithms with Deep Neural Networks for Exploring the Chemical Space](https://mlsanity.com/paper/1909.11655/) (2019)
- [Guiding Deep Molecular Optimization with Genetic Exploration](https://mlsanity.com/paper/2007.04897/) (2020)
- [MIMOSA: Multi-constraint Molecule Sampling for Molecule Optimization](https://mlsanity.com/paper/2010.02318/) (2020)
- [Reinforced Genetic Algorithm for Structure-based Drug Design](https://mlsanity.com/paper/2211.16508/) (2022)
- [Generating 3D Molecular Structures Conditional on a Receptor Binding Site with Deep Generative Models](https://mlsanity.com/paper/2010.14442/) (2020)
- [Zero-Shot 3D Drug Design by Sketching and Generating](https://mlsanity.com/paper/2209.13865/) (2022)
- [Learn molecular representations from large-scale unlabeled molecules for drug discovery](https://mlsanity.com/paper/2012.11175/) (2020)
- [TorsionNet: A Reinforcement Learning Approach to Sequential Conformer Search](https://mlsanity.com/paper/2006.07078/) (2020)

## Built on by (most cited first, 1 of 1)

- [DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization](https://mlsanity.com/paper/2403.13829/) (2024)

## Abstract (arXiv)

Structure-based drug design aims at generating high affinity ligands with prior knowledge of 3D target structures. Existing methods either use conditional generative model to learn the distribution of 3D ligands given target binding sites, or iteratively modify molecules to optimize a structure-based activity estimator. The former is highly constrained by data quantity and quality, which leaves optimization-based approaches more promising in practical scenario. However, existing optimization-based approaches choose to edit molecules in 2D space, and use molecular docking to estimate the activity using docking predicted 3D target-ligand complexes. The misalignment between the action space and the objective hinders the performance of these models, especially for those employ deep learning for acceleration. In this work, we propose MolEdit3D to combine 3D molecular generation with optimization frameworks. We develop a novel 3D graph editing model to generate molecules using fragments, and pre-train this model on abundant 3D ligands for learning target-independent properties. Then we employ a target-guided self-learning strategy to improve target-related properties using self-sampled molecules. MolEdit3D achieves state-of-the-art performance on majority of the evaluation metrics, and demonstrate strong capability of capturing both target-dependent and -independent properties.