Computational Modeling of PROTAC Ternary Complexes as Ensembles Using SILCS-xTAC.

Area of Science:

• Computational chemistry
• Drug discovery
• Structural biology

Background:

• Proteolysis targeting chimeras (PROTACs) offer a new therapeutic strategy by inducing targeted protein degradation.
• Designing PROTACs involves stabilizing interactions between target proteins and E3 ubiquitin ligases within a ternary complex.
• Current computational methods struggle with the complexity of ternary complex modeling.

Purpose of the Study:

• To develop an accurate and efficient computational method for designing PROTAC ligands.
• To address the challenge of modeling ternary complexes in drug discovery.
• To improve the prediction of PROTAC efficacy.

Main Methods:

• Utilized Site Identification by Ligand Competitive Saturation (SILCS) to generate functional group affinity patterns (FragMaps).
• Created ensembles of protein-protein interaction (PPI) dimer structures.
• Developed a SILCS-xTAC method for docking PROTACs into dimer FragMaps and scoring ternary complexes.

Main Results:

• The SILCS-xTAC method demonstrated modest correlation with experimental DC50 values across diverse systems.
• Accurate prediction of binding geometries and energetics for ternary complexes was achieved.
• The method facilitates efficient PROTAC optimization.

Conclusions:

• SILCS-xTAC is a powerful computational tool for PROTAC design and optimization.
• This method enhances the ability to target previously undruggable proteins.
• The approach advances the field of targeted protein degradation therapeutics.