Combining structure-based drug design and pharmacophores

• Published in: Journal of molecular graphics & modelling 2005-04, Vol.23 (5), p.439-446
• Main Authors: Griffith, Renate, Luu, Tien T.T., Garner, James, Keller, Paul A.
• Format: Article
• Language: English
• Subjects: Binding Sites; Computer-Aided Design; Database searching; Databases, Protein; Drug Design; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - metabolism; Human immunodeficiency virus 1; Humans; Hydrophobic and Hydrophilic Interactions; In Vitro Techniques; Ligand-based pharmacophore; Ligands; Models, Molecular; Molecular Structure; Novel pharmacophores; Proteins - chemistry; Proteins - metabolism; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-based pharmacophore
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2004.12.001

Development towards integrated computer-aided drug design methodologies is presented by utilising crystal structure complexes to produce structure-based pharmacophores. These novel pharmacophores represent the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The protein–ligand complexes can also yield information about all interactions that ligands could potentially form with the binding site, as well as about the size of the binding cavity. Together, these describe a ‘superligand’, which can also be viewed as a pharmacophore. Various types of novel pharmacophores are discussed and compared, using HIV-1 reverse transcriptase (RT) as the target protein, and their application in database searching is presented.