Structure and ligand-based design of P-glycoprotein inhibitors: a historical perspective

• Published in: Current pharmaceutical design Vol. 18; no. 27; p. 4197
• Main Authors: Palmeira, Andreia, Sousa, Emilia, Vasconcelos, M Helena, Pinto, Madalena, Fernandes, Miguel X
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 2012
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry; Computer-Aided Design; Crystallography; Drug Design; Drug Discovery; Drug Resistance, Neoplasm; Humans; Ligands; Mice; Neoplasms - drug therapy; Neoplasms - pathology; Quantitative Structure-Activity Relationship
• DOI: 10.2174/138161212802430530

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.