# Phenotypic Profile-Informed Generation of Drug-Like Molecules via Dual-Channel Variational Autoencoders

arXiv: https://arxiv.org/abs/2506.02051 · HTML: https://mlsanity.com/paper/2506.02051/

## Key facts

- Cited by 3 papers in the map (data through 14 Oct 2026).
- Builds on 8 of its 39 references that are in the map.
- First posted on arXiv 1 Jun 2025.

## Builds on (most cited first, 8 of 8)

- [Generative Adversarial Networks](https://mlsanity.com/paper/2203.00667/) (2022)
- [Empirical Evaluation of Gated Recurrent Neural Networks on Sequence Modeling](https://mlsanity.com/paper/1412.3555/) (2014)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [MolGAN: An implicit generative model for small molecular graphs](https://mlsanity.com/paper/1805.11973/) (2018)
- [Learning Deep Generative Models of Graphs](https://mlsanity.com/paper/1803.03324/) (2018)
- [Hierarchical Generation of Molecular Graphs using Structural Motifs](https://mlsanity.com/paper/2002.03230/) (2020)
- [Deep Reinforcement Learning for De-Novo Drug Design](https://mlsanity.com/paper/1711.10907/) (2017)
- [Application of generative autoencoder in de novo molecular design](https://mlsanity.com/paper/1711.07839/) (2017)

## Built on by (most cited first, 3 of 3)

- [Valid Property-Enhanced Contrastive Learning for Targeted Optimization & Resampling for Novel Drug Design](https://mlsanity.com/paper/2509.00684/) (2025)
- [Bridging the phenotype-target gap for molecular generation via multi-objective reinforcement learning](https://mlsanity.com/paper/2509.21010/) (2025)
- [PhAME: Phenotype-Aware Molecular Editing via Latent Diffusion](https://mlsanity.com/paper/2605.28226/) (2026)

## 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.