Viruses that belong to the family called Flaviviridae cause widespread illness, suffering, and death throughout the developed and developing world. These viruses are spread by insect bites or contact with contaminated blood. Dengue hemorrhagic fever, hepatitis C, West Nile encephalitis, and Yellow fever are among the most serious diseases resulting from infection with these viruses. No drugs exist to effectively treat these diseases.
- Dengue hemorrhagic fever: Each year 50–100 million people are infected with dengue virus, although this number may rise since 40% of the world is at risk for dengue virus infection. Over 1.5 million people are hospitalized with dengue fever and dengue hemorrhagic fever annually. Dengue fever is a severe, flu–like illness typically accompanied by very high fever and severe joint pain. Dengue hemorrhagic fever is a frequent complication of dengue virus infection, characterized by intense fever, internal bleeding, and circulatory failure; death occurs in 5% of patients.
- Hepatitis C: Hepatitis C virus infects approximately 3% of the world's population. Eighty percent of infected individuals develop chronic infections that progress to hepatitis, cirrhosis, liver cancer, and end–stage liver disease within 10–30 years. Hepatitis C virus is mainly transmitted by transfusion of unscreened blood products, injection drug use, needle–stick accidents, and the reuse of contaminated instruments in health care and other settings.
- West Nile encephalitis: West Nile virus is common in parts of Africa, Asia, and Europe, and was introduced into the United States in 1999. Seasonal summer/fall outbreaks of West Nile disease are now a major public health problem in the U.S. While 20% of infected people develop non–life threatening West Nile fever, one in 150 people develop severe, even fatal, diseases of the nervous system, including West Nile encephalitis and West Nile meningitis. There are no human vaccines or drugs to treat or control this disease.
- Yellow fever: Yellow fever derives its name from jaundice (yellowing of the skin and eyeballs) that results from liver failure in many infections. The Yellow fever virus is spread by mosquitoes in Africa, South America, and the Caribbean. Despite the existence of an effective vaccine, Yellow fever virus continues to cause widespread hemorrhagic illness and remains a significant public health concern in Africa and South America. Periodic epidemics result in hundreds of thousands of new infections. Yellow fever infections cause a flu–like disease, with 15% of cases progressing to a life–threatening disease accompanied by jaundice and internal bleeding. The mortality rate for Yellow fever virus infection is 7%.
Supportive care is the only option to alleviate the symptoms of these infectious diseases. Lack of antiviral drugs makes it difficult to effectively treat these and other emerging and reemerging infectious diseases. This severely burdens the fragile medical resources in developed and developing countries. Since current drug discovery approaches are very costly and time–consuming, controlling infectious disease outbreaks will remain a major health problem unless new drug discovery strategies are employed.
World Community Grid and "Discovering Dengue Drugs – Together"
Using the megacomputing power of World Community Grid, researchers at The University of Texas Medical Branch will complete extensive calculations to identify new drug–like molecules with potent antiviral activity against dengue, hepatitis C, West Nile, and Yellow fever viruses. These calculations will accurately determine how tightly small drug–like molecules bind to the different flavivirus proteases. Compounds predicted to bind tightly to viral proteases will be tested for anti–flavivirus activity.
The binding calculations combine rigorous mean–field molecular dynamics algorithms, developed by Dr. Benoit Roux and his team at the University of Chicago (Chicago, Illinois, USA), with the AutoDock virtual docking program to accurately predict how tightly small molecules bind to each flavivirus protease. AutoDock, developed by Dr. Arthur Olson of The Scripps Research Institute (San Diego, California, USA) and used in World Community Grid's FightAIDS@Home project, can predict how small molecules, such as drug candidates, might fit into a binding "pocket" on a protein with a known atomic structure. AutoDock will be used on World Community Grid to fit millions of different small molecules to the flavivirus proteases, so the best fitting molecules can be identified. These fitting calculations provide a preliminary metric to discriminate between possible protease inhibitors and non–binding molecules.
Potential protease inhibitors, as predicted by AutoDock, will be organized into a concise database for subsequent detailed analysis with CHARMM, the molecular dynamics program developed by Professor Martin Karplus and his colleagues at Harvard University (Cambridge, Massachusetts, USA). Accurate CHARMM–based binding free energy calculations (a measure of how tightly a small molecule will bind to a protein) were developed by Dr. Roux and will be applied to all potential protease inhibitors. The post–processing of the initial fitting results with binding free energy calculations will significantly reduce false–positive rates, thus speeding discovery of potent protease inhibitors. Novel compounds predicted to be high–affinity inhibitors of flavivirus proteases will be tested in laboratory assays for antiviral activity.
Running these complex drug discovery calculations on World Community Grid will dramatically reduce the time required to complete this computationally intensive project. This will speed the discovery of compounds that inhibit dengue, hepatitis C, West Nile, and Yellow fever virus replication. This is a significant step towards developing new drugs to improve global health.