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

• Main Author: Palmeira, Andreia
• Publication Date: 2012
• Other Authors: Sousa, Emilia, Vasconcelos, M. Helena, Pinto, Madalena, Fernandes, Miguel X.
• Format: Article
• Language: eng
• Source: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Download full: http://hdl.handle.net/10400.13/5019
• topic: Computer-assisted drug design; Homology modeling; P-glycoprotein inhibitors; Pharmacophore; Quantitative structure-activity relationships; Structure-based drug design; .; Faculdade de Ciências Exatas e da Engenharia

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 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.