Transformer Decoder Learns from a Pretrained ProteinLanguage Model to Generate Ligands with High Affinity

The drug discovery process can be significantly accelerated by using deep learning methods to suggest molecules with druglike features and, more importantly, that are good candidates to bind specific proteins of interest. We present a novel deep learning generative model, Prot2Drug, that learns to generate ligands binding specific targets leveraging (i) the information carried by a pretrained protein language model and (ii) the ability of transformers to capitalize the knowledge gathered from thousands of protein–ligand interactions. The embedding unveils the receipt to follow for designing molecules binding a given protein, and Prot2Drug translates such instructions by using the syntax of the molecular language generating novel compounds which are predicted to have favorable physicochemical properties and high affinity toward specific targets. Moreover, Prot2Drug reproduced numerous known interactions between compounds and proteins used for generating them and suggested novel protein targets for known compounds, indicating potential drug repurposing strategies. Remarkably, Prot2Drug facilitates the design of promising ligands even for protein targets with limited or no information about their ligands or 3D structure.