Palmeira, AndreiaSousa, EmiliaVasconcelos, M. HelenaPinto, MadalenaFernandes, Miguel X.2023-02-092023-02-092012Palmeira, A., Sousa, E., Helena Vasconcelos, M., Pinto, M., & X Fernandes, M. (2012). Structure and ligand-based design of P-glycoprotein inhibitors: a historical perspective. Current pharmaceutical design, 18(27), 4197-4214.http://hdl.handle.net/10400.13/5019Computer-assisted drug design (CADD) is a valuable approach for the discovery of new chemical entities in the field of cancer therapy. There is a pressing need to design and develop new, selective, and safe drugs for the treatment of multidrug resistance (MDR) cancer forms, specifically active against P-glycoprotein (P-gp). Recently, a crystallographic structure for mouse P-gp was obtained. However, for decades the design of new P-gp inhibitors employed mainly ligand-based approaches (SAR, QSAR, 3D-QSAR and phar macophore studies), and structure-based studies used P-gp homology models. However, some of those results are still the pillars used as a starting point for the design of potential P-gp inhibitors. Here, pharmacophore mapping, (Q)SAR, 3D-QSAR and homology modeling, for the discovery of P-gp inhibitors are reviewed. The importance of these methods for understanding mechanisms of drug resistance at a molecular level, and design P-gp inhibitors drug candidates are discussed. The examples mentioned in the review could provide insights into the wide range of possibilities of using CADD methodologies for the discovery of efficient P-gp inhibitors.engComputer-assisted drug designHomology modelingP-glycoprotein inhibitorsPharmacophoreQuantitative structure-activity relationshipsStructure-based drug design.Faculdade de Ciências Exatas e da Engenhariajournal article10.2174/138161212802430530