RESEARCH: CANCER
FOLDING PROJECT #16498 PROFILE

This project uses computer simulations to find new shapes of a protein called MET kinase that's involved in some cancers. The goal is to discover these new shapes so scientists can design better cancer drugs that work even when the cancer becomes resistant to existing treatments like crizotinib.

Note: This TLDR is a simplication and may not be 100% accurate.

In drug discovery, particularly that of cancer, maximizing state exploration is a useful novel strategy – providing new protein states and conformations to point drug design methods at increases the likelihood that a potential binder and inhibitor may be found.

However, in many cases a new state that is "useful for design" (ie.

ones distinct enough to be worth targeting to identify novel drugs) require a lot of sampling or simulation.

Sometimes, even exascale computers like Folding@home are not enough! Adaptive methods are very powerful here, but have the drawback of requiring system knowledge, or having to guess which protein features are worth adaptively exploring on, which may not always turn out to be true.

Another promising strategy, explored in these projects, is to "Accelerate" the simulations.

By broadly applying "boosters" to the simulation, we effectively "flatten" the energy landscape of a protein's conformations, allowing the protein to visit states more easily than it normally would.

Alongside the ability to discover new states that we can seed simulations of, just like adaptive sampling simulations, these boosters have specific technical and physiclal properties that allow us to infer something about a new state's "accessibility" (ie where it exists on the landscape). In projects 16497–16499 we test three such boosters to accelerate our simulations to identify how well boosted simulations work for our purposes.

Here we apply it to the protein MET kinase, a protein drug target in many cancers such as non-small-cell lung carcinoma.

MET kinase is targeted by the drug crizotinib but often evolves resistance against the drug, rendering it ineffective.

With our boosted simulations we hope to observe never before seen states of MET!.

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drug discovery

The process of identifying and developing new medications.

Drug discovery is a complex process that involves identifying promising drug candidates, testing their effectiveness and safety, and ultimately bringing them to market. This often involves a multi-disciplinary approach, combining expertise in chemistry, biology, pharmacology, and clinical research.

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cancer

A group of diseases characterized by uncontrolled cell growth.

Cancer is a broad term for a group of diseases that involve the abnormal and uncontrolled growth of cells. This can lead to the formation of tumors, which can invade surrounding tissues and spread to other parts of the body.

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protein

A large biomolecule composed of amino acids.

Proteins are essential building blocks of life, playing a vast array of roles within cells and organisms. They are responsible for transporting molecules, catalyzing reactions, providing structural support, and much more.

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drug design

The process of designing and developing new drugs.

Drug design is a multi-faceted process that involves identifying potential drug targets, understanding their structure and function, and then designing molecules that can interact with them to produce a desired therapeutic effect.

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inhibitor

A substance that blocks or reduces the activity of a specific enzyme or protein.

Inhibitors are molecules that can bind to enzymes or proteins and prevent them from carrying out their normal functions. This is often used in drug development to target specific proteins involved in disease pathways.

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MET kinase

Methionine Aminopeptidase 2 Kinase

MET kinase is a protein involved in cell growth and signaling. It plays a role in several types of cancer, making it a target for drug development.

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crizotinib

A drug that inhibits MET kinase.

Crizotinib is a type of targeted therapy used to treat certain types of lung cancer. It works by blocking the activity of the MET kinase protein, which is involved in the growth and spread of cancer cells.