Language model driven: a PROTAC generation pipeline with dual constraints of structure and property

TL;DR

This paper introduces LM-PROTAC, an AI-driven pipeline using a transformer-based model with dual constraints to design PROTAC molecules targeting specific proteins, demonstrated on Wnt3a.

Contribution

The study presents a novel language model-based pipeline with dual structure and property constraints for efficient PROTAC molecule generation.

Findings

Successfully generated PROTAC molecules targeting Wnt3a

Demonstrated the pipeline's ability to meet structural and property constraints

Validated generated molecules through in vitro experiments

Abstract

The imperfect modeling of ternary complexes has limited the application of computer-aided drug discovery tools in PROTAC research and development. In this study, an AI-assisted approach for PROTAC molecule design pipeline named LM-PROTAC was developed, which stands for language model driven Proteolysis Targeting Chimera, by embedding a transformer-based generative model with dual constraints on structure and properties, referred to as the DCT. This study utilized the fragmentation representation of molecules and developed a language model driven pipeline. Firstly, a language model driven affinity model for protein compounds to screen molecular fragments with high affinity for the target protein. Secondly, structural and physicochemical properties of these fragments were constrained during the generation process to meet specific scenario requirements. Finally, a two-round screening of the preliminary generated molecules using a multidimensional property prediction model to generate a batch of PROTAC molecules capable of degrading disease-relevant target proteins for validation in vitro experiments, thus achieving a complete solution for AI-assisted PROTAC drug generation. Taking the tumor key target Wnt3a as an example, the LM-PROTAC pipeline successfully generated PROTAC molecules capable of inhibiting Wnt3a. The results show that DCT can efficiently generate PROTAC that targets and hydrolyses Wnt3a.