Docking in the Dark: Insights into Protein–Protein and Protein–Ligand Blind Docking
Muhammad Sohaib Roomi, Giulia Culletta, Lisa Longo, Walter Filgueira de Azevedo, Ugo Perricone, Marco Tutone
Abstract
Blind docking predicts binding interactions between two molecular entities without prior knowledge of the binding site. This approach is essential because it explores the entire surface of the receptor to identify potential interaction sites. Blind docking widely works for both protein-protein and ligand-protein interaction studies. In protein-protein blind docking, the method aims to predict the correct orientation and interface of two proteins forming a complex. Protein blind docking is particularly valuable in studying transient interactions, protein-protein recognition, signaling pathways, tentative and significant biomolecular assemblies where structural data is limited. Ligand-protein blind docking discovers potential binding pockets across the entire protein surface. It is frequently applied in early-stage drug discovery, especially for novel or poorly characterized targets. The method helps identify allosteric sites or novel binding regions that are not evident from known structures. Overall, blind docking provides a versatile and powerful tool for studying molecular interactions, enabling discovery even in the absence of detailed structural information. In this scenario, we reported a timeline of attempts to improve this kind of computational approach with ML and hybrid approaches to obtain more reliable predictions. We dedicate two main sections to protein-protein and protein-ligand blind docking, presenting the reliability and caveats for each approach and outlining potential future directions.