<p>P-glycoprotein (P-gp/ABCB1) is a membrane-bound efflux transporter implicated in multidrug resistance and poor pharmacokinetics of therapeutic agents. Its ability to transport chemically diverse compounds stems from a highly dynamic conformational cycle, making rational inhibitor design particularly challenging. Here, we investigated the impact of P-gp conformational states on inhibitor binding by systematically docking a curated set of 60 inhibitors across 22 distinct P-gp structural models derived from molecular dynamics simulations of cryo-EM and AlphaFold-based structures in both apo and ligand-bound states. We elucidated how inhibitor binding profiles vary across structural states and whether distinct conformations can be preferentially exploited for inhibitor design. Known inhibitors such as tariquidar and elacridar (previously resolved in cryo-EM structures) validated the docking approach. Large macrocyclic inhibitors such as valspodar and cyclosporine preferred conformations with wider binding cavities, consistent with the need for expanded pockets to accommodate their size. These findings suggest that targeting distinct states of the P-gp transport cycle may enable more effective and selective inhibition. This work provides a structural framework to support the design of conformation-selective inhibitors of P-gp. By integrating conformational diversity with systematic docking, our study contributes to a more mechanistic understanding of P-gp modulation at the molecular level and may help guide the future design of more effective and selective P-gp inhibitors aimed at overcoming P-gp–mediated drug resistance.</p>