FightAIDS@Home is a volunteer computing project operated by the Olson Laboratory at The Scripps Research Institute. It runs on internet-connected home computers, and since July 2013 also runs on Android smartphones and tablets. [1] It aims to use biomedical software simulation techniques to search for ways to cure or prevent the spread of HIV/AIDS.
Olson's target is HIV protease, a key molecular machine of the virus that when blocked stops it from maturing. These blockers, known as "protease inhibitors", are thus a way of avoiding the onset of AIDS and prolonging life. The Olson Laboratory is using computational methods to identify new candidate drugs that have the right shape and chemical characteristics to block HIV protease. This general approach is called structure-based drug design, and according to the National Institutes of Health's National Institute of General Medical Sciences, it has already had a dramatic effect on the lives of people living with AIDS.
FightAIDS@Home makes use of the AutoDock VINA software, which tests how well a particular molecule binds to the HIV-1 protease.
In October 2015 FightAIDS@Home Phase 2 was launched, using the computationally intensive Binding Energy Distribution Analysis Method (BEDAM) to "more thoroughly evaluate the top candidates from the vast number of results generated in Phase 1". [2]
It was originally implemented using a distributed computing software infrastructure provided by Entropia. However, since May 2003 FightAIDS@Home has not been associated with Entropia, [3] and on November 21, 2005, the project moved to World Community Grid and the Entropia software was abandoned. [4]
Scripps Research Institute published its first peer-reviewed scientific paper about the results of FightAIDS@Home on April 21, 2007. [5] This paper explains that the results up to that point will primarily be used to improve the efficiency of future FightAIDS@Home calculations. [6]
On February 3, 2010, the project announced it found two compounds that make a completely new class of AIDS-fighting drugs possible: "two compounds that act on novel binding sites for an enzyme used by the human immunodeficiency virus (HIV), the virus that causes AIDS. The discovery lays the foundation for the development of a new class of anti-HIV drugs to enhance existing therapies, treat drug-resistant strains of the disease, and slow the evolution of drug resistance in the virus."
A March 2022 research paper details the results of the screening of over 1.6 million ZINC compounds at World Community Grid. First screened using AutoDock Vina, the top-scoring 500 were then analysed using BEDAM. After further screening, 24 of these were selected to perform thermal shift assays. 2 compounds appear to bind at the HIV-1 Capsid dimmer interface, possibly by occupying a new sub-pocket that has not been exploited by any existing HIV-1 capsid inhibitors. [7]
The minimum system requirements to run FightAIDS@home are: [8]
| Memory | 250 MB |
|---|---|
| Hard drive | 50 MB |
| Computer graphics | optional |
| Internet connection |
With distributed computing every computer added accelerates the project, while the program has little impact on the performance of the machine where it is installed, as the calculation process can be set to run at minimum priority in the background.
The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.
grid.org was a website and online community established in 2001 for cluster computing and grid computing software users. For six years it operated several different volunteer computing projects that allowed members to donate their spare computer cycles to worthwhile causes. In 2007, it became a community for open source cluster and grid computing software. After around 2010 it redirected to other sites.
In biology and other experimental sciences, an in silico experiment is one performed on a computer or via computer simulation software. The phrase is pseudo-Latin for 'in silicon', referring to silicon in computer chips. It was coined in 1987 as an allusion to the Latin phrases in vivo, in vitro, and in situ, which are commonly used in biology. The latter phrases refer, respectively, to experiments done in living organisms, outside living organisms, and where they are found in nature.
World Community Grid (WCG) is an effort to create the world's largest volunteer computing platform to tackle scientific research that benefits humanity. Launched on November 16, 2004, with proprietary Grid MP client from United Devices and adding support for Berkeley Open Infrastructure for Network Computing (BOINC) in 2005, World Community Grid eventually discontinued the Grid MP client and consolidated on the BOINC platform in 2008. In September 2021, it was announced that IBM transferred ownership to the Krembil Research Institute of University Health Network in Toronto, Ontario.
In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when a ligand and a target are bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using, for example, scoring functions.
Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus.
Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth once to twice a day.
Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme.
Rudi Pauwels is a Belgian pharmacologist and biotech entrepreneur.
Discovering Dengue Drugs – Together (DDDT) was a World Community Grid project launched in 2007 sponsored by scientists at the University of Texas Medical Branch at Galveston and the University of Chicago. Its goal was to identify new antiviral drugs effective against viruses from the family Flaviviridae. The project closed in 2015.
Bevirimat is an anti-HIV drug derived from a betulinic acid-like compound, first isolated from Syzygium claviflorum, a Chinese herb. It is believed to inhibit HIV by a novel mechanism, so-called maturation inhibition. It is not currently U.S. Food and Drug Administration (FDA) approved. It was originally developed by the pharmaceutical company Panacos and reached Phase IIb clinical trials. Myriad Genetics announced on January 21, 2009 the acquisition of all rights to bevirimat for $7M USD. On June 8, 2010 Myriad Genetics announced that it was halting the development of maturation inhibitors, including bevirimat, to focus more on their oncology portfolio.
Inte:Ligand was founded in Maria Enzersdorf, Lower Austria (Niederösterreich) in 2003. They established the company headquarters on Mariahilferstrasse in Vienna, Austria that same year.
LigandScout is computer software that allows creating three-dimensional (3D) pharmacophore models from structural data of macromolecule–ligand complexes, or from training and test sets of organic molecules. It incorporates a complete definition of 3D chemical features that describe the interaction of a bound small organic molecule (ligand) and the surrounding binding site of the macromolecule. These pharmacophores can be overlaid and superimposed using a pattern-matching based alignment algorithm that is solely based on pharmacophoric feature points instead of chemical structure. From such an overlay, shared features can be interpolated to create a so-called shared-feature pharmacophore that shares all common interactions of several binding sites/ligands or extended to create a so-called merged-feature pharmacophore. The software has been successfully used to predict new lead structures in drug design, e.g., predicting biological activity of novel human immunodeficiency virus (HIV) reverse transcriptase inhibitors.
Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.
AutoDock is a molecular modeling simulation software. It is especially effective for protein-ligand docking. AutoDock 4 is available under the GNU General Public License. AutoDock is one of the most cited docking software applications in the research community. It is used by the FightAIDS@Home and OpenPandemics - COVID-19 projects run at World Community Grid, to search for antivirals against HIV/AIDS and COVID-19. In February 2007, a search of the ISI Citation Index showed more than 1,100 publications had been cited using the primary AutoDock method papers. As of 2009, this number surpassed 1,200.
Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.
Topological inhibitors are rigid three-dimensional molecules of inorganic, organic, and hybrid compounds that form multicentered supramolecular interactions in vacant cavities of protein macromolecules and their complexes.
Mozenavir (DMP-450) is an antiviral drug which was developed as a treatment for HIV/AIDS. It acts as an HIV protease inhibitor and binds to this target with high affinity, however despite promising results in early testing, mozenavir was unsuccessful in human clinical trials. Studies continue into related derivatives.
In the management of HIV/AIDS, HIV capsid inhibitors are antiretroviral medicines that target the capsid shell of the virus. This is in contrast to most current antiretroviral drugs used to treat HIV, which do not directly target the viral capsid. These have also been termed "Capsid-targeting Antivirals", "Capsid Effectors", and "Capsid Assembly Modulators (CAMs)". Because of this, drugs that specifically inhibit the HIV capsid are being developed in order to reduce the replication of HIV, and treat infections that have become resistant to current antiretroviral therapies.
Exscalate4Cov was a public-private consortium supported by the Horizon Europe program from the European Union, aimed at leveraging high-performance computing (HPC) as a response to the coronavirus pandemic. The project utilized high-throughput, extreme-scale, computer-aided drug design software to conduct experiments.
