A principal odor map unifies diverse tasks in olfactory perception.

Mapping molecular structure to odor perception is a key challenge in olfaction. We used graph neural networks to generate a principal odor map (POM) that preserves perceptual relationships and enables odor quality prediction for previously uncharacterized odorants. The model was as reliable as a human in describing odor quality: On a prospective validation set of 400 out-of-sample odorants, the model-generated odor profile more closely matched the trained panel mean than did the median panelist. By applying simple, interpretable, theoretically rooted transformations, the POM outperformed chemoinformatic models on several other odor prediction tasks, indicating that the POM successfully encoded a generalized map of structure-odor relationships. This approach broadly enables odor prediction and paves the way toward digitizing odors.

Multiobjective de novo drug design with recurrent neural networks and nondominated sorting.

Research productivity in the pharmaceutical industry has declined significantly in recent decades, with higher costs, longer timelines, and lower success rates of drug candidates in clinical trials. This has prioritized the scalability and multiobjectivity of drug discovery and design. De novo drug design has emerged as a promising approach; molecules are generated from scratch, thus reducing the reliance on trial and error and premade molecular repositories. However, optimizing for molecular traits remains challenging, impeding the implementation of de novo methods. In this work, we propose a de novo approach capable of optimizing multiple traits collectively. A recurrent neural network was used to generate molecules which were then ranked based on multiple properties by a nondominated sorting algorithm. The best of the molecules generated were selected and used to fine-tune the recurrent neural network through transfer learning, creating a cycle that mimics the traditional design-synthesis-test cycle. We demonstrate the efficacy of this approach through a proof of concept, optimizing for constraints on molecular weight, octanol-water partition coefficient, the number of rotatable bonds, hydrogen bond donors, and hydrogen bond acceptors simultaneously. Analysis of the molecules generated after five iterations of the cycle revealed a 14-fold improvement in the quality of generated molecules, along with improvements to the accuracy of the recurrent neural network and the structural diversity of the molecules generated. This cycle notably does not require large amounts of training data nor any handwritten scoring functions. Altogether, this approach uniquely combines scalable generation with multiobjective optimization of molecules.