Molecular Glue-Design-Evaluator (MOLDE): An Advanced Method for In-Silico Molecular Glue Design.

Protein function modulation using small-molecule binding is an important therapeutic strategy for many diseases. However, many proteins remain undruggable due to the lack of suitable binding pockets for small-molecule binding. Proximity-induced protein degradation using molecular glues has recently been identified as an important strategy to target undruggable proteins. Molecular glues were discovered serendipitously and as such currently lack an established approach for in-silico-driven rationale design. In this work, we aim to establish an in-silico method for designing molecular glues. To achieve this, we leverage known molecular glue-mediated ternary complexes and derive a rationale for the in-silico design of molecular glues. Establishing an in-silico rationale for molecular glue design would significantly contribute to the literature and accelerate the discovery of molecular glues for targeting previously undruggable proteins. Our work presented here and named Molecular Glue-Designer-Evaluator (MOLDE) contributes to the growing literature of in-silico approaches to drug design in-silico literature.