Protein–protein interactions (PPIs) play essential roles in cellular function and have emerged as valuable, though complex, drug targets. This chapter examines the biological relevance of PPIs and the therapeutic promise of small molecules capable of modulating these interactions. It provides a focused overview of computational strategies for designing PPI inhibitors, including orthosteric, allosteric, andAnchors anchor-based approaches, with methods for predicting interfaces and identifying hot spots. Key structure-based techniques such as molecular docking and molecular dynamicsMolecular dynamics simulations are discussed, along with fragment-based and ligand-based drug designLigand-based drug design. The chapter also covers pharmacophorePharmacophore modeling, virtual screening, and the role of AI/ML tools in enhancing hit prediction and profiling. Special attention is given to the computational optimization of ADMETAbsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties, including early toxicity screening, key liability predictions, and integrated docking-ADMET workflows. The chapter concludes by highlighting the clinical landscape and offering future perspectives on the use of computational tools in advancing PPI-targeted drug discovery.