Drug Discovery in the Pharmacology at Yale University has a rich history of achievement and a strong tradition of scholarship. From the first anticancer and antiviral therapeutics to the most recent era of precisely targeted cancer drugs, aided by information using the most recent advances in individualized anticancer therapies and structure guided drug design, the drug discovery remains an important focal point of research. Another key aspect of our drug discovery program involves the identification of a broad range of new molecular targets that would ultimately allow the development of novel treatments for cancer, autoimmune, cardiovascular, psychiatric and Alzheimer’s diseases.
The drug discovery program is a multidisciplinary effort closely linked with structural biology, integrative cell signaling, and neuroscience programs to explore new approaches for therapeutics. We also have close alliances with the Department of Chemistry at Yale, the Developmental Therapeutics Program in the Yale Comprehensive Cancer Center, and translational clinical research programs to offer a unique opportunity to participate in drug discovery process from bench to bedside in a highly collaborative environment.
Drug Discovery in Pharmacology at Yale
Our drug discovery program at Yale offers a unique opportunity to be directly involved with identifying novel molecular targets and developing effective treatments. As discussed below the research of the faculty in this program spans from molecular studies to identify new targets to drugs in clinical trials as well as a number of drugs that have received FDA approval.
The first step in the process of drug discovery is to identify a molecular target that is associated with a particular disease. The next step is to establish that modulation or intervention of the function of the chosen target is associated with a reversal of the disease process. The research in integrative cell signaling and neuroscience programs in the Department of Pharmacology offers a wealth of novel molecular targets to consider for therapeutic intervention. Once a particular target is selected, a number of approaches may be taken to modulate or interfere with the biological function. These approaches might include the use of small molecules or protein biologicals such as monoclonal antibodies that alter biological activity. These efforts are aided by the Yale West Campus screening facilities: High Throughput Cell Biology (HTCB) that offers screening with RNAi and the Small Molecule Discovery Center that provides access to libraries of unique small molecules. We work closely with the Structural Biology program in Pharmacology to obtain the detailed three-dimensional structure of the target along with novel ligands as lead compounds that affect function. Structural biology also assists in lead optimization to obtain candidate compounds that are suitable for further investigation. Possible candidate molecules are further examined in preclinical studies and the most promising compounds would ultimately be examined in clinical trials in humans. Our department offers a number of courses to provide an understanding of how the drug discovery process works from the identification of molecular targets and therapeutic candidates to the design of clinical trials in humans.
About the Image
The activity of the pro-inflammatory protein macrophage migration inhibitory factor (MIF) is modulated by the non-competitive inhibitor ibudilast and its derivative AV1013. These compounds bind in an allosteric cleft not seen in the unbound MIF structure. The allosteric site is proximal to the active site, explaining the mode of inhibition. Image courtesy of Yoonsang Cho. Image from the Lolis lab.
About the Image
The electron density of quisqualate bound to the ligand binding domain of an AMPA receptor point mutant (GluA2 T686A). Image from the Howe Lab.
About the Image
Inhibitor of parasitic TS-DHFR enzyme discovered by virtual library screening. Image from the Anderson lab.