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.
Drug Discovery Image Gallery
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- 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.
- This chemical was discovered by the Cheng lab, together with two laboratories in Japan, as a potential anti-HIV drug for the treatment of AIDS patients. Festivinar targets HIV-RT. However, the proposed binding site of Festivinar on HIV-RT is difficult to mutate without losing RT activity. Thus, the clinical resistance as the result of HIV-RT mutation will be difficult for the virus. Based on Phase I/II studies by Oncolys, which licensed the compound from Yale University, encouraging anti-HIV results were observed. The chemical has just been licensed by Bristol Myers Squibb for a Phase II clinical trial.
- The electron density of quisqualate bound to the ligand binding domain of an AMPA receptor point mutant (GluA2 T686A). Image from the Howe Lab.
- In wild type p53 cells, DNA damage induces p53R2, which replaces R2 to form ribonucleotide reductase (RNR) and supplies dNTPs for DNA repair. In p53 null or mutant cells, R2 is retained to form RNR and supply dNTPs for DNA repair. The Sartorelli laboratory has had a longstanding interest in RNR and has developed several potent inhibitors with significant anticancer activity.
- Crystal 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 3σ 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.
- Inhibitor of parasitic TS-DHFR enzyme discovered by virtual library screening. Image from the Anderson lab.
- PHY906 is made based on an 1800 year old Chinese medicine formula. Pre-clinical studies from the Cheng lab showed it to decrease G.I. toxicity and enhance anticancer activities of a variety of chemotherapeutic drugs. Multiple mechanisms of action resulting from different chemicals in the formula were observed. Together with PhytoCeutica, Inc., a Yale sponsored company of which Dr. Cheng is a co-founder, it was shown that PHY906 could be made consistently and demonstrated promising clinical activities during Phase I/II clinical trials in the United States for three types of cancer patients. Phase II/III trials are currently being planned.