RESEARCH: DUD-E
FOLDING PROJECT #12201 PROFILE

This project uses computer simulations to study how proteins interact with small molecules, like drugs. They're focusing on a protein called Acetylcholinesterase, which is important for the nervous system and is targeted by pesticides and medicines. By simulating these interactions accurately, researchers can better understand how drugs work and develop new ones more efficiently.

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 Drugs - experimental data

DUD-E is a collection of protein and small molecule pairs used to evaluate the accuracy of computer models predicting how well molecules bind to proteins. It's important for drug discovery because it helps researchers test and improve their methods.

---

protein-ligand interactions

The binding of a protein and a small molecule (ligand)

Protein-ligand interactions are essential for many biological processes, including how drugs work. When a drug binds to a specific protein, it can change the protein's function. This is what makes drugs effective in treating diseases.

---

Alpha Fold

Artificial intelligence system for protein structure prediction

AlphaFold is a powerful computer program that can predict the 3D shape of proteins. This is incredibly useful for drug discovery because it allows researchers to see how potential drugs might interact with their target proteins.

---

drug discovery

The process of identifying and developing new drugs

Drug discovery is a complex and lengthy process that involves many steps, from identifying potential drug targets to testing and manufacturing the final product. It's a crucial area of research because it leads to new treatments for diseases.

---

pesticide

A chemical used to kill pests, such as insects, weeds, or fungi

Pesticides are chemicals designed to eliminate unwanted organisms. They're widely used in agriculture to protect crops from damage but can also have negative impacts on the environment and human health.

---

Acetylcholinesterase (AChE)

An enzyme that breaks down acetylcholine, a neurotransmitter

Acetylcholinesterase is an important enzyme in the nervous system. It breaks down acetylcholine, a chemical messenger that transmits signals between nerve cells. Some drugs work by inhibiting acetylcholinesterase, which increases the levels of acetylcholine in the brain.

---

Torpedo Californica

The scientific name for the Pacific Electric Ray

Torpedo Californica is a species of ray known for its electric organs. Researchers have studied this animal extensively because it provides valuable insights into the nervous system and neurotransmission.