RESEARCH: CANCER
FOLDING PROJECT #17645 PROFILE

This project explores new ways to find promising drug targets for cancer. Traditional methods can be slow and inefficient. The project tests different 'seeding' techniques that use multiple starting points to explore the vast landscape of protein shapes, aiming to find useful drug-binding sites faster.

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. Identifying druggable states or exploring conformational state space relevant to disease is an existing challenge.

The embarassingly parallel nature of Folding@home allows us to massively scale up our exploration.

However, the underlying methods still rely on luck to a large extent – we must discover the states in work units as the dataset grows in size and more work units are run.

This can be an incredibly inefficient process, wasting work units on regions of state space that are irrelevant or uninteresting to the question at hand.

Adaptive Seeding is a way to tackle this inefficiency.

Rather than applying a "boost" potential that alters the physics of our system, or having to do live-streamed analysis like Adaptive sampling, Adaptive Seeding sets up multiple starting structures across conformational space.

The intention is that having multiple distinct starting structures will increase the rate at which the landscape is traversed and lead to transitions/pathways connecting functional states in less simulation time, while preserving physics.

These projects seek to test different "seeding" approaches that yielded a different spread of starting structures.

Each unique structure starts at a different RUN.

As with other projects, we will be studying MET kinase.

17645: Run using starting structures generated using AI-methods like AlphaFold2
17646: Run using starting structures that are stemmed from "fixing" experimentally derived structures in the PDB.

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drug discovery

The process of identifying and developing new medications.

Drug discovery is a complex multi-stage process involving the identification of potential drug candidates, testing their efficacy and safety, and ultimately bringing them to market for patient use. It's a crucial aspect of the pharmaceutical industry, aiming to develop treatments for various diseases.

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cancer

A group of diseases characterized by uncontrolled cell growth and spread.

Cancer is a broad term for diseases where abnormal cells grow uncontrollably. These cells can invade nearby tissues and spread to other parts of the body through the bloodstream or lymphatic system. There are many types of cancer, each with unique characteristics and treatments.

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protein

Large biomolecules essential for various cellular functions.

Proteins are the workhorses of cells, carrying out a vast array of tasks. They are made up of chains of amino acids and have specific three-dimensional structures that determine their function. Proteins are involved in everything from catalyzing reactions to transporting molecules to providing structural support.

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drug design

The process of designing and developing new drugs.

Drug design is a multidisciplinary field that uses scientific principles to create new medications. It involves understanding the molecular mechanisms of disease, identifying potential drug targets, and designing molecules that interact with these targets in a desired way.

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inhibitor

A substance that blocks or reduces the activity of a biological molecule.

Inhibitors are molecules that can interfere with the function of enzymes, proteins, or other biomolecules. They are often used in drug development to target specific pathways involved in disease.

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simulation

The process of using computer models to mimic real-world phenomena.

Simulation involves creating mathematical or computational representations of systems and processes. It's used in various fields, including drug discovery, to study the behavior of molecules and predict their interactions.

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Adaptive Seeding

Adaptive Seeding

Adaptive Seeding is a computational technique used in drug discovery to explore conformational space more efficiently. It involves starting multiple simulations from different protein conformations to increase the likelihood of finding relevant states.

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RUN

A single instance of a program execution.

RUN is a term often used in computing to refer to a single execution of a program or script. Each RUN typically starts with specific inputs and produces an output based on the program's instructions.