Medicinal chemists on the Drug Discovery & Development team are working to improve current therapies and develop new treatments for patients with schizophrenia and related brain disorders.
A multi-step drug discovery process built on research findings
We are engaged in an iterative process of designing and synthesizing novel molecules, based on data generated by our team. We then analyze these compounds for their desired effects on specific enzymes, receptors, ion channels and other drug targets implicated in schizophrenia and related brain disorders.
We also must consider what the final product is designed to do. For devising a new, more effective therapy for schizophrenia, our overall objective is to generate a compound that can be taken orally once a day, can penetrate the blood-brain barrier, is selective in its action, and persists in the brain long enough to have the desired effect. The fundamental components of our drug discovery process are design, synthesis, testing, and analysis.
In the design phase of drug discovery, we take into account all of the accumulated data about a lead molecule as it progresses through a series of more and more stringent assays. We identify the properties of the molecule that need improvement, and consider chemical modifications that are likely to affect those properties.
We do careful analyses of structure-activity relationships, coupled with computer modeling of predicted chemical properties to ensure we are making drug-like molecules. During the design process, we consider more than just potency in the initial screening assay, as we prepare and purify small-molecule drugs that can be taken orally and penetrate the blood-brain barrier, thus entering the brain freely.
Once we have designed a molecule, we need to devise a way to make, or synthesize, the compound. At the Lieber Institute, we are continually developing new organic chemistry methods, including variations on existing methods, which allow us to optimize the preparation of target molecules. We use a sequence of multiple chemical steps that differ for each target molecule, which are often prepared in a parallel format to maximize productivity. Once synthesized, each compound is then purified and characterized prior to testing in various biological and chemical assays.
After synthesizing and purifying a new molecule, we test it for activity on the enzyme, receptor, or ion channel of interest. Testing methods differ and are specific to the target. The next steps are to evaluate molecules with sufficient activity in more rigorous, sequential assays designed to narrow down candidates for eventual in vivo testing.
Once the novel compounds have been tested, we identify those with sufficient activity in a series of assays, which vary by and are specific to the project. At this stage of analysis, medicinal chemists assess the desirable characteristics of a compound—such as its potency, selectivity, and pharmacokinetics. In particular, we need to identify molecular properties that need improvement in the next round of design and testing.
Data gained through these and other methodologies is fed back into the design of new compounds, and the entire design, synthesis, testing and analysis process is repeated until we identify a molecule with all the right properties. Depending on the desired profile of the compound, it may take many iterations of this drug discovery cycle to produce the right compound. This process may take many steps, but we are continually learning more with each step along the way.
LIBD Speaker Series: Jeremy J. Day Ph.D.
“Control-Alter-Delete: Gene Regulatory Mechanisms in Brain Reward Circuitry” Jeremy J. Day, Ph.D. Associate Professor Department of Neurobiology Evelyn F. McKnight Brain Institute & The University of Alabama at Birmingham When: February 11, 2020 2:00pm-3:00pm Where: The Lieber Institute for Brain Development Rangos […]