RESEARCH: CANCER
FOLDING PROJECT #18705 PROFILE

VHL syndrome causes tumors due to a faulty gene. This project uses computer simulations to design PROTACs, molecules that can target and destroy the problematic protein. By simulating how PROTACs bind to proteins, researchers can find the best designs for experiments, making drug development faster and more efficient.

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

Von Hippel-Lindau (VHL) syndrome is a rare disease that causes tumors and cysts to develop and grow in the body.

These tumors usually are non-cancerous, but some, especially tumors that develop in the kidney and pancreas, may become cancerous.

VHL syndrome is caused by a mutation in the VHL gene, which decreases the VHL protein’s ability to act as an E3 ligase and ubiquitinate the α subunit of hypoxia-inducible factor (HIF), which decreases proteolysis of HIF proteins.

The elevated HIF levels are responsible for the hypervascularization in renal cell carcinoma associated with the VHL syndrome disease state.

This project investigates the design of heterobifunctional molecules, also known as PROteolysis TArgeting Chimeras (PROTACs), which can bind both the VHL and HIF2α and help regulate the degradation of HIF2α.

Experimental measurements can provide insights to the challenge of PROTAC optimization, but the design space is too large to test every potential molecule design.

Therefore, molecular dynamic simulations will be run on potential ligand candidates to reduce the amount of possible PROTAC hits and reduce the experiments necessary for validation.

Initially the warhead domain, the PROTAC’s binding domain to HIF2α, will be developed by running simulations using various different structures already bound to the protein and determining the stability of the bound state for each potential structure.

Then the linker region, the structure that connects the two binding domains, of the PROTAC will be developed by running simulations to determine the ternary structure for the VHL-PROTAC- HIF2α complex.

All the computed values of kon, koff, ΔH, ΔS, and ΔG use AMBER force fields for Protein-Protein and Protein-Ligand's interactions.

Roivant is using published PROTAC-bound ternary complexes, plus some data generated internally for the F@h projects, and all simulation data is being made publicly available.

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Von Hippel-Lindau (VHL) syndrome

A rare genetic disorder causing tumor growth.

Von Hippel-Lindau syndrome is a rare inherited disease that causes tumors to grow in various parts of the body. These tumors can be non-cancerous but may sometimes become cancerous. The condition is caused by mutations in the VHL gene, which affects how the body regulates cell growth and division.

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Tumor

An abnormal mass of tissue that results from uncontrolled cell growth.

A tumor is a collection of abnormal cells that grow and multiply uncontrollably. Tumors can be benign (non-cancerous) or malignant (cancerous). Benign tumors usually remain localized while cancerous tumors can spread to other parts of the body.

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Cyst

A closed sac or cavity containing fluid or semi-solid material.

A cyst is a sac-like structure filled with fluid, air, or other substances. Cysts can occur in various parts of the body and may be harmless or symptomatic depending on their location and size.

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Gene

A unit of heredity that carries genetic information.

Genes are the fundamental units of heredity. They are segments of DNA that contain instructions for building and maintaining an organism. Each gene carries specific information that determines traits such as eye color, hair texture, and susceptibility to certain diseases.

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Protein

A large biomolecule composed of amino acids.

Proteins are essential macromolecules that perform a wide range of functions in living organisms. They act as enzymes, structural components, hormones, and antibodies. Proteins are made up of chains of amino acids linked together by peptide bonds.

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Mutation

A permanent change in the DNA sequence.

A mutation is a alteration in the DNA sequence of an organism. Mutations can be caused by errors during DNA replication or exposure to environmental factors such as radiation. Some mutations have no effect while others can lead to genetic disorders.

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PROteolysis TArgeting Chimeras (PROTACs)

A class of heterobifunctional molecules that target proteins for degradation.

PROTACs are innovative drug candidates designed to degrade specific proteins by hijacking the cellular protein degradation machinery. They consist of two parts: a ligand that binds to the target protein and a ligand that binds to an E3 ligase, which promotes protein degradation.

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Molecular Dynamic Simulations

Computer simulations that model the movement and interactions of molecules over time.

Molecular dynamic simulations are computational methods used to study the behavior of molecules at the atomic level. These simulations can provide insights into protein folding, drug-target interactions, and other biological processes.