Many crucial biochemical processes rely on intricate networks of protein-protein interactions (PPIs). It is widely acknowledged that almost half of the proteome in eukaryotes consists of proteins containing intrinsically disordered regions (IDRs). These IDRs are characterized as contiguous segments of 20 or more amino acid residues that remain unstructured under native conditions. Notably, IDRs play a pivotal role in numerous PPIs. Frequently, an IDR undergoes a disorder-to-order transition upon binding to another protein, resulting in the formation of a low-affinity, high-selectivity protein-protein complex. It is well documented that PPIs play a crucial role in the pathogenesis of diverse and complex diseases, such as cancers, diabetes, and neurodegenerative disorders. Unsurprisingly, modulation of PPIs with small molecules is an appealing drug discovery strategy. However, targeting PPIs with small-molecule drugs has proven to be a formidable challenge, with only a limited number of such inhibitors successfully becoming approved drugs over the past quarter century. A deeper understanding of how to design small molecules that emulate PPI recognition mechanisms, such as folding of a protein IDR upon binding, may unlock new strategies for developing drug candidates, and new possibilities for effective interventions in complex disease processes. This report focusses on unravelling the molecular driving forces of a disorder-to-order transition of a protein IDR induced by a small molecule. Targeting the p53/MDM2 proteinprotein interaction is a well-established anticancer strategy and several small-molecule inhibitors have reached late-stage clinical trials. However, the emergence of drug resistance due to mutations in p53 or MDM2 has underscored the need for developing next-generation inhibitors. Most p53/MDM2 inhibitors bind to the N-terminal domain of MDM2, which consists of a core structured region, and an IDR referred to as a 'lid' (Figure ). AM-7209, a clinical candidate compound belonging to a family of piperidinone molecules, uniquely orders the N-terminal 'lid' of MDM2 upon binding (Figure ). Previous work from our group has elucidated why AM-7209 selectively bind to the ordered-lid conformation of MDM2, whereas other compound classes bind without ordering the lid. Here we achieve a deep understanding of the molecular driving forces that underpin AM-7209:lid recognition by performing a combination of molecular dynamics (MD) simulations, isothermal titration calorimetry (ITC) experiments and nuclear magnetic resonance (NMR) measurements. Significantly, we identify a crucial amino residue in the intrinsically disordered lid of MDM2 that modulates AM-7209 affinity by up to three orders of magnitude. These insights provide valuable design principles for targeting future IDRs with small molecules and highlight the potential role of IDRs in drug-resistance mechanisms.