QSAR-Guided Generative Framework for the Discovery of Synthetically Viable Odorants

TL;DR

This paper introduces a QSAR-guided VAE framework that efficiently generates novel, syntactically valid odorant molecules with high structural diversity from limited training data, advancing de novo molecular design for fragrances.

Contribution

It combines a VAE with QSAR modeling to generate odorants from small datasets, enabling extensive chemical space exploration and structural novelty.

Findings

100% validity of generated molecules confirmed

94.8% of generated molecules are unique

74.4% of candidates have novel core frameworks

Abstract

The discovery of novel odorant molecules is key for the fragrance and flavor industries, yet efficiently navigating the vast chemical space to identify structures with desirable olfactory properties remains a significant challenge. Generative artificial intelligence offers a promising approach for \textit{de novo} molecular design but typically requires large sets of molecules to learn from. To address this problem, we present a framework combining a variational autoencoder (VAE) with a quantitative structure-activity relationship (QSAR) model to generate novel odorants from limited training sets of odor molecules. The self-supervised learning capabilities of the VAE allow it to learn SMILES grammar from ChemBL database, while its training objective is augmented with a loss term derived from an external QSAR model to structure the latent representation according to odor probability. While the VAE demonstrated high internal consistency in learning the QSAR supervision signal, validation against an external, unseen ground truth dataset (Unique Good Scents) confirms the model generates syntactically valid structures (100\% validity achieved via rejection sampling) and 94.8\% unique structures. The latent space is effectively structured by odor likelihood, evidenced by a Fr\'echet ChemNet Distance (FCD) of $\approx$ 6.96 between generated molecules and known odorants, compared to $\approx$ 21.6 for the ChemBL baseline. Structural analysis via Bemis-Murcko scaffolds reveals that 74.4\% of candidates possess novel core frameworks distinct from the training data, indicating the model performs extensive chemical space exploration beyond simple derivatization of known odorants. Generated candidates display physicochemical properties ....