The drug discovery pipeline, from target selection through launch. The DDP conducts work at the lead optimization stage.

Introduction to the DDP – A Mission Statement:The NIH is currently supporting the generation of chemical libraries and small molecule screening centers to identify lead candidates that interact with molecular targets. However, an important, missing element in translating candidate molecules to the clinic is the medicinal chemistry that develops the lead structures that are identified from these early screening efforts. Optimizing chemical hits for clinical trial is commonly referred to as lead optimization . The refinement in structure is necessary in order to improve potency, selectivity, pharmacokinetic properties, safety (ADMET properties), and pharmaceutics.

The DDP fills this niche by creating a medicinal chemistry core comprised of both synthetic organic/medicinal chemists and molecular modelers who are able to refine lead candidates interacting with neurologically significant biological targets. Employing rational drug design principles, and cutting edge modeling methods including in silico ADME, the DDP undertakes iterative rounds of chemical synthesis and testing to create compounds of improved potency and selectivity that can serve as drug candidates in the treatment of various disorders including cancer, CNS disorders, and neglected diseases. Many of the biological studies are performed in partnership with collaborating biologists located in universities or in biotech companies. The DDP thus has the capability to make a real difference in the lives of patients, for it will be able to assist in the evolution of “hits” identified in screening efforts and to turn them into real drugs. As drug discovery is a high risk undertaking, one that often requires years of investment prior to reaching a true clinical candidate, it will be important that a high level of commitment exists between the collaborating biologists and the DDP in order to achieve the common goal of creating new therapies for unmet medical needs. The DDP thus become a major vehicle through which chemists and biologists can reduce to practice their novel findings and ideas for creating the next generation of therapies for neurological disorders.

General Aspects of Medicinal Chemistry/Drug Discovery . Drug discovery and development remains a challenging area of research, as many barriers must be overcome to take a drug to the clinic (1). In addition to establishing potency and efficacy for a specific CNS target or targets, there is a need to satisfy considerations relating to the pharmacokinetic and safety profiles of any new chemical entities including, in particular, their ability to penetrate the blood-brain-barrier (ADMET properties). Minimization of off-target interactions is also important to limiting the side effects of any new chemical.

Effective drug discovery and development requires that one be skilled not only in the art of organic synthesis, but that one also has a strong grasp of the principles of medicinal chemistry. Many of these skills come through experience gained from working on a number of medicinal chemistry problems, in an effort to identify ligands that interact with a chosen molecular target, and that in turn bring about a desired outcome, behavioral or otherwise, in in vivo animal models of the disease. From a lead structure, the medicinal-organic chemist designs analogs that may show a heightened affinity for the target, while minimizing structural features that may cause undesirable toxicity, or result in inappropriate PK features, such as rapid metabolism, insolubility, or inability to penetrate the blood-brain-barrier. The experienced medicinal chemist has generally learned what type of functional group s can best be added to improve upon compound activity/selectivity, while avoiding those features likely to cause toxicity.

In cases where x-ray structural information or homology models of the molecular target are available, molecular modeling programs can be used to aid in the drug design process by further narrowing the number of structures that need to be made to identify a true drug candidate (2). For example, an idea of the size of a receptor binding pocket would immediately set limits as to the bulk of appendages that may be added to the scaffold of the lead candidate, as group s that are too large would interfere sterically with the walls of the binding site. Therefore, in carrying out the medicinal chemistry efforts within the DDP we will make use of molecular modeling when appropriate to help guide our synthetic work and compound design.

One of the basic tenets of medicinal chemistry is that biological activity is dependent on the three-dimensional placement or orientation of specific functional group s (the pharmacophore) appended to a molecular scaffold. Structure-based design is one of the most common techniques to be used in drug design. The development of molecular modeling programs and their application in pharmaceutical research has been formalized as a field of study known as computer assisted drug design (CADD) or computer assisted molecular design (CAMD). Structure-based design refers specifically to identifying and complementing the 3D structure (in particular, the binding pocket or active site) of a target molecule such as a receptor protein or enzyme. Chemists can be assisted in the design process by having an idea of the general shape and charge character required for a small molecule to complement the 3-dimensional shape of the active site. Also, the existence of a set of lead compounds can be used in concert with the knowledge of the protein structure to further direct the course of the discovery work. As with all model building, however, the chemist's intuition and training is necessary to interpret the results appropriately. Comparison of modeling results with the experimental data, where available, is also important to guide both the laboratory and computational work. Drug design is by its very nature a complex undertaking that requires an iterative process of synthesis and testing. The research begins when a biologist identifies a compound that displays an interesting biological profile, and after a number of design, synthesis, and assay cycles, the process ends when both the activity profile and the chemical synthesis of the new chemical entity are optimized.

Optimization with respect to ADME/Tox properties of new chemical entities should be taken into account at an early stage of the drug discovery process to steer the synthetic efforts in a direction that will result in a useful clinical entity . In silico ADMET modeling has taken on a more significant role recently due to the advances in chemical descriptors and computational power. For design purposes, the medicinal chemist can make use of medicinal chemistry filters to eliminate troublesome functionality, while maintaining solubility, metabolic stability, cell-permeability, etc., all of which are required to create a clinical candidate. Drug discovery is an extremely complex undertaking, and it has been estimated that 15 years of effort are required to go from the bench to the marketplace.

Licensing

The UIC Drug Discovery program actively works with its technology transfer office to patent its active compounds. Spin-off companies and licensing to larger pharmaceutical companies are exploited in advancing our New Chemical Entities to the clinic.

    -Dr. Alan Kozikowski, Ph. D.

See the list of awarded patents

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