Targeted Protein Degradation: Advances, Challenges, and Prospects for Computational Methods

Abstract

The therapeutic approach of targeted protein degradation (TPD) is gaining momentum due to its potentially superior effects compared with protein inhibition. Recent advancements in the biotech and pharmaceutical sectors have led to the development of compounds that are currently in human trials, with some showing promising clinical results. However, the use of computational tools in TPD is still limited, as it has distinct characteristics compared with traditional computational drug design methods. TPD involves creating a ternary structure (protein−degrader−ligase) responsible for the biological function, such as ubiquitination and subsequent proteasomal degradation, which depends on the spatial orientation of the protein of interest (POI) relative to E2-loaded ubiquitin. Modeling this structure necessitates a unique blend of tools initially developed for small molecules (e.g., docking) and biologics (e.g., protein−protein interaction modeling). Additionally, degrader molecules, particularly heterobifunctional degraders, are generally larger than conventional small molecule drugs, leading to challenges in determining drug-like properties like solubility and permeability. Furthermore, the catalytic nature of TPD makes occupancy-based modeling insufficient. TPD consists of multiple interconnected yet distinct steps, such as POI binding, E3 ligase binding, ternary structure interactions, ubiquitination, and degradation, along with traditional small molecule properties. A comprehensive set of tools is needed to address the dynamic nature of the induced proximity ternary complex and its implications for ubiquitination. In this Perspective, we discuss the current state of computational tools for TPD. We start by describing the series of steps involved in the degradation process and the experimental methods used to characterize them. Then, we delve into a detailed analysis of the computational tools employed in TPD. We also present an integrative approach that has proven successful for degrader design and its impact on project decisions. Finally, we examine the future prospects of computational methods in TPD and the areas with the greatest potential for impact.

Degraders in epigenetic therapy: PROTACs and beyond

“…developed a surface plasmon resonance (SPR)-based assayfor the quantification of PROTAC ternary complexe stability through the measurement of kinetics associated with their formation and dissociation 193 . Researchers have also constructed an extensive modeling framework that enables: (1) the assessment of PROTACs based on precise degradation metrics, (2) the guidance of crucial compound parameters, and (3) the establishment of a connection between degradation and downstream pharmacodynamic effects 194 . Zhao et al .…”

Structural Basis of Conformational Dynamics in the PROTAC-Induced Protein Degradation

“…15 To discriminate between productive and unproductive ternary complexes, the whole CRL ligase complex was modelled to predict target protein ubiquitination based on the proximity of the target surface exposed lysine residues to the C-terminal of ubiquitin. 17–19 While avidity and cooperativity were shown to drive protein degradation, 20, 21 it was also known that increased ternary complex stability or rigidity need not correlate with increased degradation efficiency, 16 revealing the complicated role of conformational dynamics.…”

Innovative, combinatorial and high-throughput approaches to degrader synthesis

“…At this point, semi-rigid or constrained linkers such as piperazine, piperidine, spiro-bicyclic moieties or combinations of several saturated alkyl ring systems can be introduced for gradual rigidification to improve physicochemical properties and to identify lead molecules. Despite an emphasis on rational approaches, 8 the majority of PROTAC design and optimisation still relies on empirical methods, with a general strategy often involving extensive iterations of trial and error. 9…”