2025/06/01 by Hui Liu, Liu, Hui, Shiye Tian +3 · 2 citations
Biochemistry, Genetics and Molecular Biology · Engineering · #Artificial Intelligence (cs.AI) #Biomolecules (q-bio.BM) #Cell Image Analysis Techniques #FOS: Biological sciences #FOS: Computer and information sciences #Image Processing Techniques and Applications #Machine Learning (cs.LG) #Spectroscopy Techniques in Biomedical and Chemical Research
paper · pdf · doi:10.48550/arxiv.2506.02051
openalex publication_date 2025/06/01 · openalex created_date 2025/10/14 · openalex updated_date 2026/07/28
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.