AI-driven transcriptome profile-guided hit molecule generation

$Denovo$ generation of bioactive and drug-like hit molecules is a pivotal goal in computer-aided drug discovery. While artificial intelligence (AI) has proven adept at generating molecules with desired chemical properties, previous studies often overlook the influence of disease-specific cellular environments. This study introduces GxVAEs, a novel AI-driven deep generative model designed to produce hit molecules from transcriptome profiles using dual variational autoencoders (VAEs). The first VAE, ProfileVAE, extracts latent features from transcriptome profiles to guide the second VAE, MolVAE, in generating hit molecules. GxVAEs aim to bridge the gap between molecule generation and the biological context of disease, producing molecules that are biologically relevant within specific cellular environments or pathological conditions. Experimental results and case studies focused on hit molecule generation demonstrate that GxVAEs surpass current state-of-the-art methods, in terms of reproducibility of known ligands. This approach is expected to effectively find potential molecular structures with bioactivities across diverse disease contexts.