Trapping moving targets with small molecules.
Structure-based drug design traditionally uses static protein models as inspirations for focusing on "active" site targets. Allosteric regulation of biological macromolecules, however, is affected by both conformational and dynamic properties of the protein or protein complex and can potentially lead to more avenues for therapeutic development. We discuss the advantages of searching for molecules that conformationally trap a macromolecule in its inactive state. Although multiple methodologies exist to probe protein dynamics and ligand binding, our current discussion highlights the use of nuclear magnetic resonance spectroscopy in the drug discovery and design process.
Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), 600 16th Street, Box 2280, San Francisco, CA 94158-2280, USA.
Gregory M
GM
Lee
Charles S
CS
Craik
D000494:Allosteric Regulation; D000495:Allosteric Site; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides; D050882:CREB-Binding Protein / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000068877:Imatinib Mesylate; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D054852:Small Molecule Libraries; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
D001059:Apoproteins; D001549:Benzamides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D008024:Ligands; D010879:Piperazines; D011506:Proteins; D011743:Pyrimidines; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; D050882:CREB-Binding Protein; D051736:Proto-Oncogene Proteins c-mdm2; D011505:Protein-Tyrosine Kinases