Structural Pharmacology
From the time of the first visualizations of atomic-level protein structures scientists have worked towards the goal of using a detailed three-dimensional understanding of molecular structure for drug discovery. Now, the intersection of pharmacology with structural biology guides the rational design of therapeutics. This is done in small-molecule drug discovery where, for example, enzyme inhibitors can be optimized using structural biology techniques as a guide. Structural biology can also guide the discovery of new therapeutic mechanisms, for example designing targeted antibodies to alter cytokine signal transduction. The Department of Pharmacology at Yale is at the forefront of using structural biology to discover new mechanisms and targets for drug discovery. There are ongoing collaborative efforts within the department between scientists interested in Drug Discovery, Signal transduction and Neuroscience.
A prominent example that used the structural biology techniques X-ray crystallography, electron microscopy and small-angle X-ray scattering, is the discovery of a membrane-proximal region of receptor tyrosine kinases that can be targeted with antibody-based therapeutics. Our interdisciplinary graduate program provides a unique and compelling environment for graduate students to become exposed to the tools of structural biology and their utilization in the drug discovery process.
Structural Pharmacology Image Gallery
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SB14Inhibitor of parasitic TS-DHFR enzyme discovered by virtual library screening. Image from the Anderson lab. SB15Crystal structure of the cruzain•inhibitor complex (PDB ID 3IUT) elucidates the binding mode of the inhibitor in the cruzain substrate-binding site. Cruzain residues are colored pale cyan and the inhibitor is colored grey. The unbiased mFo-DFc electron density for the inhibitor is shown in violet, contoured at the 3s level. This orally bioavailable inhibitor is effective for the treatment of Chagas disease in a mouse model of this life-threatening parasitic disease. Image from the Ellman lab. SB16A model of murine CXCR2 bound to MIP-2. Image from the Lolis Lab. SB17The electron density of quisqualate bound to the ligand binding domain of an AMPA receptor point mutant (GluA2 T686A). Image from the Howe Lab. SB14Inhibitor of parasitic TS-DHFR enzyme discovered by virtual library screening. Image from the Anderson lab. SB15Crystal structure of the cruzain•inhibitor complex (PDB ID 3IUT) elucidates the binding mode of the inhibitor in the cruzain substrate-binding site. Cruzain residues are colored pale cyan and the inhibitor is colored grey. The unbiased mFo-DFc electron density for the inhibitor is shown in violet, contoured at the 3s level. This orally bioavailable inhibitor is effective for the treatment of Chagas disease in a mouse model of this life-threatening parasitic disease. Image from the Ellman lab. SB16A model of murine CXCR2 bound to MIP-2. Image from the Lolis Lab. SB17The electron density of quisqualate bound to the ligand binding domain of an AMPA receptor point mutant (GluA2 T686A). Image from the Howe Lab. SB14Inhibitor of parasitic TS-DHFR enzyme discovered by virtual library screening. Image from the Anderson lab. SB15Crystal structure of the cruzain•inhibitor complex (PDB ID 3IUT) elucidates the binding mode of the inhibitor in the cruzain substrate-binding site. Cruzain residues are colored pale cyan and the inhibitor is colored grey. The unbiased mFo-DFc electron density for the inhibitor is shown in violet, contoured at the 3s level. This orally bioavailable inhibitor is effective for the treatment of Chagas disease in a mouse model of this life-threatening parasitic disease. Image from the Ellman lab. SB16A model of murine CXCR2 bound to MIP-2. Image from the Lolis Lab. SB17The electron density of quisqualate bound to the ligand binding domain of an AMPA receptor point mutant (GluA2 T686A). Image from the Howe Lab.