Harnessing Allostery to Modulate Protein–Protein Interactions: From Function to Therapeutic Innovations

Abstract

Protein-protein interactions (PPIs) are ubiquitous mediators of cellular functions, and their dysregulation is central to numerous pathological conditions. Traditional drug discovery strategies targeting PPIs directly have faced considerable obstacles due to their extensive, flat, and dynamic interfaces, deemed conventionally “undruggable”. Allosteric regulation offers an alternative route, allowing modulation of these critical interactions through spatially distinct regulatory sites that can dynamically alter protein function without direct interference at the interface. Recent advances in computational methodologies, particularly enhanced molecular dynamics simulations and machine learning approaches, have significantly expanded our ability to identify and characterize cryptic allosteric sites and pathways. This perspective provides a comprehensive analysis of the evolving understanding of allosteric mechanisms in PPIs, highlights recent successes in computational identification and targeting of allosteric modulators, and outlines the challenges and opportunities in translating these insights into therapeutic strategies. Ultimately, this approach heralds a transformative potential in therapeutic interventions targeting complex biological networks.