A Deep Generative Model for the Inverse Design of Transition Metal Ligands and Complexes

Deep generative models yielding transition metal complexes (TMCs) remain scarce despite the key role of these compounds in industrial catalytic processes, anticancer therapies, and the energy transition. Compared to drug discovery within the chemical space of organic molecules, TMCs pose further challenges, including the encoding of chemical bonds of higher complexity and the need to optimize multiple properties. In this work, we developed a generative model for the inverse design of transition metal ligands and complexes, based on the junction tree variational autoencoder (JT-VAE). After implementing a SMILES-based encoding of the metal-ligand bonds, the model was trained with the tmQMg-L ligand library, allowing for the generation of thousands of novel, highly diverse monodentate (κ¹) and bidentate (κ²) ligands, including imines, phosphines, and carbenes. Further, the generated ligands were labeled with two target properties reflecting the stability and electron density of the associated homoleptic iridium TMCs: the HOMO-LUMO gap (ϵ) and the charge of the metal center (q _Ir). This data was used to implement a conditional model that generated ligands from a prompt, with the single- or dual-objective of optimizing either or both the ϵ and q _Ir properties and allowing for chemical interpretation based on the optimization trajectories. The optimizations also had an impact on other chemical properties, including ligand dissociation energies and oxidative addition barriers. A similar model was implemented to condition ligand generation by solubility and steric bulk.