Chemical Biology and Medicinal Chemistry

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In a nutshell

Lifting the hood on human cells

Imagine if you could peer into one of the 40 trillion cells in the human body like you were lifting the hood of a car. Inside you would see a whirring engine of life, made up of thousands of different, complex, and interacting parts. How could you tell what each part did, and which were the most important ones? Specialized research “mechanics” explore the actions of proteins and other molecules inside cells.

Chemical biologists create tools and ways to probe this sub-microscopic engine. They block the activity of some parts or prods others to action to see the effects. They tag parts to track their roles. They capture pictures of engine systems in action; taking systems apart and putting them back together to learn how they work.

Medicinal chemists use the knowledge gained from all that prodding and poking to try to fix the cell’s complex machinery when it sputters or overheats in disease. Or, in the case of viruses, bacteria, and other bugs, to turn their motors off. This means making drugs that will affect only those misfiring or infectious germs’ parts.

Chemical biology

Chemical biologists work at the interface of chemistry and biology to create and apply chemical tools and approaches to answer key questions about biological functions.

These chemical tools are used to inhibit or activate protein molecules, manipulating biological systems in order to understand them at increasing levels of detail. This approach also labels and quantifies molecules, tracking their activity.

Researchers probe, then decipher, the complex machinery of the proteome—the tens of thousands of different proteins that sequentially interact in a multitude of vital biological pathways.

Department scientists routinely focus on enzymes—proteins that selectively catalyze metabolic reactions. This work ranges from discovery of their functions and substrates to detailing of their mechanisms and kinetics.

Medicinal chemistry

Medicinal chemists seek to treat or prevent diseases by discovering and synthesizing small molecules that will selectively bind to target proteins and therapeutically alter their activity.

The department’s basic research validates these key molecular targets for intervention and develops leads for new or more effective medications.

But the discovery of potential targets (hits) is only the start of a highly iterative process by which drug leads are developed. Researchers follow up with rounds of screening, simulation, analysis, redesign, and more testing. The chemistry of the target molecule is modified in order to:

  • Enhance affinity (reduce dosage).
  • Increase selectivity (reduce off-target binding that causes side effects).
  • Improve efficacy (including pharmacokinetic properties that allow it to reach its target in the body)

Department scientists apply rational drug design methods that are guided by detailed analyses of biological systems and target proteins. They focus on discovering and improving molecules such as analogs of known binders and enzyme substrates, or those with geometries and electrostatics that complement target binding sites.

These efforts are aided by the development of computational models of molecule docking as well as high-throughput screening—automated assays that allow the simultaneous testing of tens of thousands of potential effector molecules (ligands).

Challenges include