RESEARCH: DUD-E
FOLDING PROJECT #12202 PROFILE

This project uses computer simulations to study how proteins interact with small molecules, like drugs. They're focusing on proteins from the DUD-E dataset, which has been used to test and improve protein prediction methods. One example is Acetylcholinesterase, a protein important for nervous system function that's targeted by pesticides and some medicines.

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

In this series of projects we are simulating proteins that are part of the DUD-E benchmark data set for protein-ligand interactions, using simulations initialized from Alpha Fold. Simulation methods to study protein-small molecule interactions are of critical importance to the early stages of drug discovery, but most methods have a poor balance of accuracy relative to cost.

Much of the development process for new compounds happens via screening large libraries of compounds for activity against target proteins believed to be relevant for a disease.

Lending focus to this search makes developing new molecules into drugs more economical and faster. In order to do this kind of methods development, good reference data that is widely available is essential.

A classic dataset for benchmarking structural methods attempting to predict protein-ligand interactions known as DUD-E has been widely used because it has diverse proteins, and each protein is bound to a fairly large collection (usually more than fifty) of small molecules for which the ability to bind the receptor have been measured experimentally.

Using Folding@Home, we will create large reference quality simulations of these proteins.

Because we know how such simulations, and the binding methods we or others may test on them, should look and function we have a great yardstick for improving the methods we have and developing new ones. In this project series we have the following systems, many of which are known for their medical relevance in addition to having been extensively studied with both simulation and experiment in the past. 12201 - ACES: Acetylcholinesterase that is critical to nervous system function in animals.

It is the target of pesticides, and also numerous drugs.

If targeted in the correct way, it can reduce neural swelling.

This sequence happens to be from the Pacific Electric ray, Torpedo Californica, which was a landmark discovery in biomedical efforts to isolate neurotransmitter receptors and led to a mechanistic understanding of myasthenia gravis. 12202 - AKT2: serine-threonine kinase taking part in the insulin signal transduction pathway.

Implicated in some cancers, it has been a target of drug development campaigns in the past. 12203 - AMPC: A critical antibiotic resistance gene, it is a beta lactamase capable of opening the critical structural feature of celphalosporin-type antibiotics, rendering them ineffective. 12204 - BACE1: Beta secretase 1, an aspartic acid protease that helps form myelin sheaths in neurons.

It is the major generator of amyloid-beta peptides in neurons, and therefore is implicated in Alzheimer's disease. 12205 - BRAF: B-raf is involved in sending signals involved in cell growth, and as such is considered a proto-oncogen.

It is a serine/threonine kinase that has several known inhibitors, some of which are now anti-cancer medications. 12206 - CASP3: a caspase-type protease that participates in the execution of apoptosis, the process of programmed cell death.

It also acts to cleave one of the amyloid forming proteins and is therefore implicated in Alzheimer's dementia. 12207 - CDK2: one of the cyclin dependent kinases, this protein is a checkpoint kinase that signals transitions between growth and DNA synthesis phases in the cell cycle.

Dysfunction in this checkpoint is associated with cancer; inhibiting CDK2 can arrest cell cycle in cases of abmormal growth, so it has been an anti-cancer target for some time. 12208 - CSF1R: Colony stimulating factor 1 receptor, when bound by cognate ligands, will promote survival, proliferation and differentiation of many myeloid cell types.

It is thus involved in disease and is targeted in therapies for cancer, neurodegenerative diseases, nad inflammatory bone diseases. 12209 - DPP4: Dipeptidyl peptidase-4, a protein that cuts up certain other proteins on the surfaces of most cells.

Important in immune regulation, signal transduction, and apoptosis, molecules inhibiting its enzymatic activity can help treat type 2 diabetes because the peptide hormones (GLP-1, and GIP) are degraded by DPP4.

Thus, inhibiting DPP4 prolongs the effects of these hormones. 12210 - EGFR: Epidermal growth factor receptor; its deficient signaling is associated with Alzheimer's dementia, whereas its over-expression is a common characteristic of tumor cells.

It is thus an oncogene that is targeted by numerous anti-cancer molecules and drugs.

Many of these are targeted at the tyrosine kinase domain, because hampering its function prevents excessive transduction of the signals these receptors would otherwise send to the nucleus of the tumor cell. 12211 - ESR1: Estrogen Receptor Alpha is critical to many tissue differentiation processes across the body, and has been targeted by various drugs to both enhance and suppress its effects depending on associated conditions.

12212 - FA10: Coagulation factor X is an enzyme in the coagulation signaling cascade for forming blood clots.

It is a serine endopeptidase, and has been targeted by inhibitors to reduce coagulation in medical contexts where that is desirable.
.

---

DUD-E

Directory of Useful Decoys Enhanced

DUD-E is a publicly available dataset used to benchmark and evaluate the performance of computational methods for predicting protein-ligand interactions. It contains diverse proteins each bound to a large collection of small molecules with experimentally measured binding affinities.

---

Protein-ligand interactions

The specific binding between a protein and a small molecule (ligand).

Protein-ligand interactions are crucial for many biological processes, including enzyme function, signal transduction, and drug action. Understanding these interactions is essential for developing new drugs and therapies.

---

Drug discovery

The process of identifying and developing new medications.

Drug discovery is a complex and time-consuming process that involves multiple stages, from target identification to clinical trials. It aims to develop safe and effective treatments for various diseases.

---

AlphaFold

A deep learning system that predicts the 3D structure of proteins.

AlphaFold is a groundbreaking AI system developed by DeepMind that has revolutionized protein structure prediction. It uses machine learning to accurately predict the 3D shape of proteins from their amino acid sequence, providing valuable insights into protein function and disease mechanisms.

---

Folding@Home

A distributed computing project that uses volunteer computer resources to simulate protein folding.

Folding@Home is a citizen science project that harnesses the power of many computers to perform simulations of protein folding. These simulations help researchers understand how proteins fold into their complex 3D structures, which is essential for their function.

---

Acetylcholinesterase

An enzyme that breaks down the neurotransmitter acetylcholine.

Acetylcholinesterase is a crucial enzyme in the nervous system. It breaks down acetylcholine, a neurotransmitter involved in muscle contraction and nerve impulse transmission. Acetylcholinesterase inhibitors are used to treat conditions like Alzheimer's disease.

---

Pesticides

Chemicals used to kill or control pests.

Pesticides are widely used in agriculture to protect crops from insects, weeds, and diseases. While they can be effective, their use can also have negative environmental and health impacts.

---

Neurotransmitter

A chemical messenger that transmits signals between neurons.

Neurotransmitters are essential for communication within the nervous system. They allow neurons to transmit signals to each other, enabling processes like muscle movement, thought, and emotion.