H. Martin Seidel, Ph.D.
John J. Isbell, Ph.D.
Director of Analytical Sciences and DMPK
At GNF, our medicinal chemists are involved in nearly every aspect of the drug discovery process, from early hit identification to full scale lead optimization. We utilize modern organic synthesis, directed library synthesis, state-of-the-art computational chemistry/cheminformatics, structure-based drug design, and high throughput analytical technology to facilitate drug discovery efforts throughout all phases of the process. Working with an interdisciplinary team including biologists, computation chemists, and x-ray crystallographers, we use a data-intensive approach to design, synthesize, and optimize lead molecules, developing our initial screening hits into viable clinical candidates for the treatment of human disease.
Medicinal Chemistry Approach
The key to an effective drug discovery effort is having good chemical starting points, and, at GNF, good chemical starting points derive from our powerful lead discovery infrastructure. The heart of our lead discovery technology platform is a high throughput screening system with a throughput of more than one million wells per day and a library of more than 1.7 million compounds that enables the identification of high quality screening hits. As part of the lead selection process, our medicinal chemists help identify and select multiple ‘lead-like’ scaffolds from the screening hits. These scaffolds then serve as substrates for exploratory chemistry efforts, the goals of which are 1) to enhance their potency and selectivity and 2) to evaluate them using strict criteria that define the "drug-likeness" of a lead series (e.g., cell-based efficacy, pharmacokinetic and safety profiles, pharmaceutical properties, etc.). This latter process is guided in part by a battery of in vitro and in vivo profiling assays designed to define absorption, distribution, metabolism, elimination, and toxicological (ADMET) properties as well as efficacy of the candidate molecules. Once projects advance to full lead optimization, scientists use these data along with biochemical and cell-based structure-activity information to choose compounds for testing in models of human disease. Armed with these data, GNF chemists make intelligent, data-driven decisions to optimize and identify safe and effective clinical candidates, typically within 12-18 months of the identification of a lead series. During this phase, the team typically synthesizes and evaluates hundreds to thousands of compounds from several structural classes.
Chemistry Tools Available at GNF
Among the discovery tools available to GNF chemists are routine access LC-MS and mass-triggered prep HPLC, parallel microwave synthesis, automated flash chromatography, high-field NMR, web-based compound registration, and web-based access to structural, analytical, and biological data. In addition, our chemistry technology specialists develop new tools and methods that can be broadly applied to the synthesis and purification of compounds. A key achievement has been streamlining the synthesis of combinatorial chemistry libraries. This includes new chemistries aimed at libraries of biologically relevant small molecules as well as new tools for the synthesis and purification of these libraries. The latter includes instruments, parallel synthesis, and cleavage tools and parallel compound purification systems. In addition, improved methods for the annotation, plating, storage and retrieval of compounds have been developed.
Analytical Chemistry Capabilities
Our Analytical Chemistry team at GNF is focused primarily on developing and implementing cutting-edge, high throughput (HT) technologies necessary to meet the needs of Medicinal Chemistry, Biology, and Pharmacology for sample analysis, purification, and sample handling. Accordingly, our analytical chemistry effort emphasizes leveraging analytical technologies to accelerate GNF's drug discovery effort. Our HT purification capabilities encompass both walk-up use by medicinal chemists with a few hundred samples as well as expert user access for high volume sample processing of hundreds of samples per day.
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