title: Structure and ligand-based design of P-glycoprotein inhibitors: a historical perspective.
abstract: Computer-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 pharmacophore 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.
authors: Departamento de Quimica, Laboratorio de Quimica Organica e Farmaceutica, Faculdade de Farmacia, Universidade do Porto, Portugal.
authors: Andreia
authors: A
authors: Palmeira
authors: Emilia
authors: E
authors: Sousa
authors: M Helena
authors: MH
authors: Vasconcelos
authors: Madalena
authors: M
authors: Pinto
authors: Miguel X
authors: MX
authors: Fernandes
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D003461:Crystallography; D015195:Drug Design; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008024:Ligands