# Bridging the phenotype-target gap for molecular generation via multi-objective reinforcement learning

arXiv: https://arxiv.org/abs/2509.21010 · HTML: https://mlsanity.com/paper/2509.21010/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 10 of its 42 references that are in the map.
- First posted on arXiv 25 Sep 2025.

## Builds on (most cited first, 10 of 10)

- [Neural Architecture Search with Reinforcement Learning](https://mlsanity.com/paper/1611.01578/) (2016)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Graph Convolutional Policy Network for Goal-Directed Molecular Graph Generation](https://mlsanity.com/paper/1806.02473/) (2018)
- [GuacaMol: Benchmarking Models for De Novo Molecular Design](https://mlsanity.com/paper/1811.09621/) (2018)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [Phenotypic Profile-Informed Generation of Drug-Like Molecules via Dual-Channel Variational Autoencoders](https://mlsanity.com/paper/2506.02051/) (2025)
- [Docking-based generative approaches in the search for new drug candidates](https://mlsanity.com/paper/2312.13944/) (2023)

## Abstract (arXiv)

The de novo generation of drug-like molecules capable of inducing desirable phenotypic changes is receiving increasing attention. However, previous methods predominantly rely on expression profiles to guide molecule generation, but overlook the perturbative effect of the molecules on cellular contexts. To overcome this limitation, we propose SmilesGEN, a novel generative model based on variational autoencoder (VAE) architecture to generate molecules with potential therapeutic effects. SmilesGEN integrates a pre-trained drug VAE (SmilesNet) with an expression profile VAE (ProfileNet), jointly modeling the interplay between drug perturbations and transcriptional responses in a common latent space. Specifically, ProfileNet is imposed to reconstruct pre-treatment expression profiles when eliminating drug-induced perturbations in the latent space, while SmilesNet is informed by desired expression profiles to generate drug-like molecules. Our empirical experiments demonstrate that SmilesGEN outperforms current state-of-the-art models in generating molecules with higher degree of validity, uniqueness, novelty, as well as higher Tanimoto similarity to known ligands targeting the relevant proteins. Moreover, we evaluate SmilesGEN for scaffold-based molecule optimization and generation of therapeutic agents, and confirmed its superior performance in generating molecules with higher similarity to approved drugs. SmilesGEN establishes a robust framework that leverages gene signatures to generate drug-like molecules that hold promising potential to induce desirable cellular phenotypic changes. The source code and datasets are available at: https://github.com/hliulab/SmilesGEN.