RESEARCH: PROTEIN-SIMULATION-DUD-E-BENCHMARK
FOLDING PROJECT #12280 PROFILE

This project uses computer simulations to study how proteins interact with small molecules. These interactions are important for drug development. Scientists will use a large dataset of proteins and molecules called DUD-E to create high-quality simulations. This will help them develop new and better methods for predicting how drugs work.

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. 12234 - 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. 12235 - 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. 12236 - 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. 12237 - 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. 12238 - 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. 12239 - 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. 1240 - 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. 12241 - 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. 12242 - 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. 12243 - 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. 12244 - 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.

12245 - 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.
12246 - FABP4: Fatty Acid Binding protein 4 is a protein that imports lipids between intra and extracellular membranes in macrophages and adipocytes.

Inhibiting it is associated with both preventing certain fat-tumor cancers and metabolic syndromes. 12247 - GRIA2: Glutamate ionotropic receptor AMPA type subunit 2 is a glutamate receptor, an essential neurotransmitter in humans.

Its pre-mRNA is A->I edited at a particular site that makes the channel impermeable to calcium.

Editing errors here can result in ALS, and some other diseases. 12248 - HSP90AA1: Heat shock protein 90kDa alpha A1 is a stress inducible protein that refolds misfolded or damaged proteins.

It is a relevant drug target because it interacts with a number of tumor promoting proteins and plays a large role in cellular adaptation to stress. 12249 - IGF1R: Insulin like growth factor 1 is an extracellular receptor with a tyrosine kinase domain.

It is critical for growth and development, and as such if overproduced can contribute to the cancer phenotype and certain other diseases.

Therefore inhibitors have been developed to target this extracellular receptor. 12250 - ITAL (LFA-1): Leukocyte adhesion cglycoprotein LFA-1 alpha is an integrin found on lymphocytes and other leukocytes.

It functions in the process of tissue emigration in lymphocytes, and in cytotoxic T-cell mediated killing of cells. 12251 - KIT: tyrosine-protein kinase KIT is a receptor tyrosine kinase and a proto-oncogene.

It senses cytokines, transducing signals that govern cell proliferation and survival.

As such it is often mutated in cancers, where its excessive activity maintains or enhances the tumor state. 12252 - MAPK2: Mitogen-activated protein kinase kinase is part of the MAPK pathway, which is famously aberrant in many types of cancers, particularly melanomas.

Inhibitors against it would slow the progression of cancer, so it has been targeted by therapies historically. 12253 - MET: tyrosine-protein kinase Met, also known as hepatocyte growth factor receptor, governs embryonic development, organogenesis and wound-healing.

Abnormal activation of MET sustains tumors by causing them to grow and become better supplied by blood vessels.

Extensive research has focused on inhibiting MET because of its correlation with poor prognosis in cancer, and many compounds are in various parts of the regulatory approval process. 12254 - MK10: MAPK-10 or mitogen-activated protein kinase 10 is associated with a wide variety of cellular processes associated with proliferatiation, differentiation, and development.

Mapk-10 is implicated in neuronal development, and when active can inhibit neuronal apoptosis.

12255 - MK14: MAPK-14 or p38-alpha is another stress and differentiation controlling kinase.

Because of its interaction with inflammatory signaling in the immune system, it is a relevant target for immune diseases and heart disease. 12256 - PPARD: Peroxisome proliferator-activated receptor delta is a nuclear hormone receptor that is implicated in the development of several classes of chronic disease.

Drugs stimulating it can act as biochemical substitutes for exercise, and decouple oxidative phosphorylation.

12257 - PPARG: Peroxisome proliferator activated receptor gamma is similar to the delta variant in some ways, but also serves as a master-regulator of fat cell differentiation.

It has been studied as a target for growth inhibition in cancer cell cultures.

It also is targeted by drugs that treat lipid metabolism disorders like hyperlipidemia and hyperglycemia, as well as for type 2 diabetes as an insulin sensitizer. 12258 - PTN1: Tyrosine-protein phosphatase non-receptor type 1 counteracts the effect of certain tyrosine kinases in protein signalling.

One of its targets is the phosphosite on the insulin receptor and several other receptor tyrosine kinases, including some from this list.

As such, it has implications for both the treatemnt of some cancers and also type 2 diabetes. 12259 - RENI: Renin is an endopeptidase that generates angiotensin 1, resulting in a blood pressure increasing signalling cascade that also causes sodium retention by the kidneys.

As such, renin inhibitors can serve to reduce blood pressure. 12260 - RXRA: Retinoid x receptor alpha is a nuclear receptor that binds retinoic acid, causing transcription of a large number of genes.

12261 - TGFR1: Transforming growth factor beta receptor 1 is a TGF-beta receptor that regulates differentiation in a number of endothelial cell types, and seems to have particular bearing on the development of reproductive tissues.

It has been targeted by studies working to develop cancer therapeutics. 12262 - THRB: Thyroid hormone receptor beta is a nuclear receptor that, when activated by thyroid hormone, initiates a large number of different genes.

Deficiencies in activity can result in thyroid hormone resistance which can cause goiter.

12263 - TRY1: Trypsin-1 is the main form of trypsinogen secreted by the pancreas.

It is an enzyme that breaks down proteins, and defective mutations of it can cause pancreatitis.

It is also a workhorse protein in modern biochemical and biophysical labs. 12264 - TRYB1: Tryptase beta-1 is a trypsin like protease that is secreted as part of Mast-cell activation.

As such it has roles in inflammation associated with asthma, and in cleaving flu's hemagglutinin surface protein (which initiates the experience of flu-like symptoms).

Attempts to produce inhibitors hve so far been difficult, but it has relevance to reducing the severity of the inflammatory response in these conditions. 12265 - VGFR2: Vascular endothelial growth factor receptor number 2 is a tyrosine kinase signaling receptor that binds the vascularization hormone, and causes tissue remodeling to form channels for blood vessel growth.

When over-active or over-expressed this protein supports the vascularization of tumor tissue, making inhibitors targeting it helpful in treating some cancers. 12267 - ABL1: ABL is a protein tyrosine kinase and a prominent proto-oncogen.

Mu
tations in this gene are involved in chronic and acute myelogenous leukemia (A/CML),
and it is the kinase in the fusion protein created by the translocation event that
causes the Philadelphia chromosome, a historically important type of hereditary canc
er risk factor that was visible from analysis of mitotic chromosomes.

Specific treat
ment of these cancers came in part from the development of tyrosine kinase inhibito
rs targeting this protein.
12268 - ANDR: The androgen receptor.

A steroid hormone activated transcription f
actor, it activates a collection of genes that are part of the secondary sex charact
eristics.

Implicated in several varieties of human disease, androgen receptor can no
tably undergo gene duplication events in cancer cells, causing aberrant growth in th
e presence of androgen.

Newer treatments for such cancers involve blocking this rece
ptor.
12270 - FAK1: Focal adhesion kinase.

A protein tyrosine kinase involved in the signaling pathways that cause cells to adhere to one another.

Excess activity is often part of cancer phenomena, and is implicated in metastasis.

It is also cleaved in the 'caspase' cascade resulting in programmed cell death, so this activity is sometimes disrupted in cancers, particularly breast cancers and certain types of ovarian cancers.

A specific class of drugs has emerged to inhibit this molecule as anti-cancer therapies.
12271 - FKBP1: FK506 (tacrolimus) binding protein.

An enzyme that takes part in immune regulation and basic cell processes.

It is the target of immunosuppresive drugs; it may also take part in the dysfunctions in cell signalling associated with some cancers.

Originally discovered as the target of the immunosuppresant tacrolimus used in organ transplants.
12272 - GCR: Glucocorticoid receptor.

Binds cortisol and other glucocorticoid hormones.

Many medications target this receptor because of the changes in gene expression activation or repression of its behavior can induce.
12273 - GLCM: Beta glucocerebrosidase (also called acid beta glucosidase).

An enzyme catalyzing a reaction in glycolipid metabolism; some of its mutants are implicated in parkinsons disease, and Gaucher's disease, a lysozomal storage disease.
12274 - HXK4: Hexokinase IV (glucokinase).

Occurring in the liver and pancreas, and is critical for carbohydrate metabolism in mammals.

An enzyme transcribed in response to insulin signaling, it is relevant for treatment of certain types of diabetes.

Genetic variation can result in genetic diseases similar to diabetes.
12276 - LCK: Lymphocite specific protein tyrosine kinase.

Responsible for the T-cell receptor signalling cascade. 12278 - MCR: Mineralocorticoid receptor.

MR is expressed in many tissues, and does myriad things.

It is activated by aldosterone and glucocorticoids like cortisol.

Targeting MR has relevance for numerous medically relevant biologies, but has been exploited for hypertension/cardiovascular disease.
12279 - PPARA: Peroxisome proliferator-activated receptor.

A receptor activated under conditions of energy deprivation--necessary for ketogenesis, whereby energy is produced from fats while an organism fasts.
12280 - PRGR: Progesterone Receptor.

This receptor binds a key sex hormone having to do with pregnancy and estrous in mammals.

Activating or deactivating this receptor pharmaceutically has been very important for contraceptives and other reproduction-related applications.
12281 - PUR2: GAR transformylase, Phosphoribosylglycinamide formyltransferase.

This enzyme is a critical part of nucleic acid biosynthesis.

Because nucleotides are the building blocks of DNA and RNA, cells that are very metabolically or mitotically active depend on this enzyme more heavily.

As such, this protein is the target of some chemotheraputic treatments.

proteins

Large biological molecules essential for various bodily functions.

Proteins are the workhorses of our bodies, involved in everything from building tissues to fighting infections. They are made up of chains of amino acids and perform a wide variety of tasks.

DUD-E

Directory of Useful Decoys for Enhanced Evaluation of Docking performance.

DUD-E is a database used to evaluate the accuracy of computer programs that predict how drugs bind to proteins. It contains diverse sets of molecules and their interactions with proteins.

protein-ligand interactions

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

Protein-ligand interactions are crucial for many biological processes. Drugs often work by interacting with specific proteins to modulate their activity.

drug discovery

The process of identifying and developing new medications.

Drug discovery is a complex and lengthy process involving research, testing, and clinical trials to bring new drugs to market. It aims to develop safe and effective treatments for diseases.

Alpha Fold

A deep learning algorithm for protein structure prediction.

AlphaFold is a revolutionary AI system that can accurately predict the 3D shape of proteins. This has immense implications for drug discovery and understanding biological processes.

simulations

Computer models that mimic real-world processes.

Simulations are used in various fields to study complex systems. In biotechnology, they help researchers understand protein behavior and drug interactions.

Folding@Home

A distributed computing project that uses idle computer processing power to run protein folding simulations.

Folding@Home is a citizen science initiative where volunteers contribute their computer's processing power to accelerate research on protein folding.

Acetylcholinesterase

An enzyme that breaks down acetylcholine, a neurotransmitter.

Acetylcholinesterase plays a crucial role in nerve signal transmission. Its inhibition can lead to the accumulation of acetylcholine, which has therapeutic effects in some neurological disorders.