Center for Drug Discovery

Boston, MA, United States

Center for Drug Discovery

Boston, MA, United States
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SMU researchers and game developers are partnering with the world's vast network of gamers in hopes of discovering a new cancer-fighting drug. Biochemistry professors Pia Vogel and John Wise in the SMU Department of Biological Sciences, and Corey Clark, deputy director of research at SMU Guildhall, are leading the SMU assault on cancer in partnership with fans of the popular best-selling video game "Minecraft." Vogel and Wise expect deep inroads in their quest to narrow the search for chemical compounds that improve the effectiveness of chemotherapy drugs. "Crowdsourcing as well as computational power may help us narrow down our search and give us better chances at selecting a drug that will be successful," said Vogel. "And gamers can take pride in knowing they've helped find answers to an important medical problem." Up to now, Wise and Vogel have tapped the high performance computing power of SMU's Maneframe, one of the most powerful academic supercomputers in the nation. With ManeFrame, Wise and Vogel have sorted through millions of compounds that have the potential to work. Now, the biochemists say, it's time to take that research to the next level—crowdsourced computing. A network of gamers can crunch massive amounts of data during routine gameplay by pairing two powerful weapons: the best of human intuition combined with the massive computing power of networked gaming machine processors. Taking their research to the gaming community will more than double the amount of machine processing power attacking their research problem. "With the distributed computing of the actual game clients, we can theoretically have much more computing power than even the supercomputer here at SMU," said Clark, also adjunct research associate professor in the Department of Biological Sciences. SMU Guildhall in March was named No. 1 among the Top 25 Top Graduate Schools for Video Game Design by The Princeton Review. "If we take a small percentage of the computing power from 25,000 gamers playing our mod we can match ManeFrame's 120 teraflops of processing power," Clark said. "Integrating with the 'Minecraft' community should allow us to double the computing power of that supercomputer." Even more importantly, the gaming community adds another important component—human intuition. Wise believes there's a lot of brainpower eager to be tapped in the gaming community. And human brains, when tackling a problem or faced with a challenge, can make creative and intuitive leaps that machines can't. "What if we learn things that we never would have learned any other way? And even if it doesn't work it's still a good idea and the kids will still get their endorphin kicks playing the game," Wise said. "It also raises awareness of the research. Gamers will be saying 'Mom don't tell me to go to bed, I'm doing scientific research." The Vogel and Wise research labs are part of the Center for Drug Discovery, Design and Delivery (CD4) in SMU's Dedman College. The center's mission is a novel multi-disciplinary focus for scientific research targeting medically important problems in human health. Their research is funded in part by the National Institutes of Health. Vogel and Wise have narrowed a group of compounds that show promise for alleviating the problem of chemotherapy failure after repeated use. Each one of those compounds has 50 to 100—or even more—characteristics that contribute to their efficacy. "Corey's contribution will hopefully tell us which dozen perhaps of these 100 characteristics are the important ones," Vogel said. "Right now of those 100 characteristics, we don't know which ones are good ones. We want to see if there's a way with what we learn from Corey's gaming system to then apply what we learn to millions of other compounds to separate the wheat from the chaff." James McCormick—a fifth year Ph.D. student in cellular molecular biology who earned his doctoral degree this spring and is a researcher with the Center for Drug Discovery, Design and Delivery—produced the data set for Clark and Guildhall. Lauren Ammerman, a first-year Ph.D. student in cellular and molecular biology and also working in the Center for Drug Discovery, Design and Delivery, is taking up the computational part of the project. Machine learning and algorithms by themselves don't always find the best solution, Clark said. There are already examples of researchers who for years sought answers with machine learning, then switched to actual human gamers. Gamers take unstructured data and attack it with human problem-solving skills to quickly find an answer. "So we're combining both," Clark said. "We're going to have both computers and humans trying to find relationships and clustering the data. Each of those human decisions will also be supplied as training input into a deep neural network that is learning the 'human heuristic'—the technique and processes humans are using to make their decisions." Gamers already have proven they can solve research problems that have stymied scientists, says Vogel. She cites the video game "Foldit" created by the University of Washington specifically to unlock the structure of an AIDS-related enzyme. Some other Games With A Purpose, as they're called, have produced similar results. Humans outperform computers when it comes to tasks in the computational process that are particularly suited to the human intellect. "With 'Foldit,' researchers worked on a problem for 15 years using machine learning techniques and were unable to find a solution," Clark said. "Once they created the game, 57,000 players found a solution in three weeks." Gamers will access the research problem using the version of Minecraft they purchased, then install a "mod" or "plugin"—gamer jargon for modifying game code to expand a game's possibilities—that incorporates SMUs research problem and was developed in accordance with Minecraft terms of service. Players will be fully aware of their role in the research, including ultimately leaderboards that show where players rank toward analyzing the data set in the research problem. SMU is partnering with leaders in the large Minecraft modding community to develop a functioning mod by the end of 2017. The game will be heavily tested before release to the public the second quarter of 2018, Clark said. The SMU Minecraft mod will incorporate a data processing and distributed computing platform from game technology company Balanced Media Technology (BMT), McKinney, Texas. BMT's HEWMEN software platform executes machine-learning algorithms coupled with human guided interactions. It will integrate Wise and Vogel's research directly into the SMU Minecraft mod. SMU Guildhall will provide the interface enabling modders to develop their own custom game mechanic that visualizes and interacts with the research problem data within the Minecraft game environment. Guildhall research is funded in part by Balanced Media Technology. "We expect to have over 25,000 people continuously online during our testing period," Clark said. "That should probably double the computing power of the supercomputer here." That many players and that much computing power is a massive resource attacking the research problem, Wise said. "The SMU computational system has 8,000 computer cores. Even if I had all of ManeFrame to myself, that's still less computing and brainpower than the gaming community," he said. "Here we've got more than 25,000 different brains at once. So even if 24,000 don't find an answer, there are maybe 1,000 geniuses playing 'Minecraft' that may find a solution. This is the most creative thing I've heard in a long time."

Janero D.R.,Center for Drug Discovery | Thakur G.A.,Northeastern University
Expert Opinion on Drug Discovery | Year: 2016

Introduction: Allosteric modulators of G-protein coupled receptors (GPCRs) hold the promise of improved pharmacology and safety over typical orthosteric GPCR ligands. These features are particularly relevant to the cannabinoid receptor 1 (CB1R) GPCR, since typical orthosteric CB1R ligands are associated with adverse events that limit their translational potential. Areascovered: The contextual basis for applying allostery to CB1R is considered from pharmacological, drug-discovery, and medicinal standpoints. Rational design of small-molecule CB1R allosteric modulators as potential pharmacotherapeutics would be greatly facilitated by direct experimental characterization of structure-function correlates underlying the biological activity of chemically-diverse CB1R allosteric modulators, CB1R allosteric ligand-binding binding pockets, and amino acid contact residues critical to allosteric ligand engagement and activity. In these regards, designer covalent probes exhibiting well-characterized molecular pharmacology as CB1R allosteric modulators are emerging as valuable molecular reporters enabling experimental interrogation of CB1R allosteric site(s) and informing the design of new CB1R agents as drugs. Expertopinion: Synthesis and pharmacological profiling of CB1R allosteric ligands will continue to provide valuable insights into CB1R structure-function correlates. The resulting data should expand the repertoire of novel agents capable of exerting therapeutic benefit by modulating CB1R-dependent signaling. © 2016 Informa UK Limited, trading as Taylor & Francis Group.

News Article | September 23, 2016

Researchers with the Virginia Tech Center for Drug Discovery have identified a compound that blocks the growth of a fungus that causes deadly lung infections and allergic reactions in people with compromised immune systems. The research team targeted the switch that allows the fungus Aspergillus fumigatus to survive in iron-deficient conditions like the human body. Specifically, they targeted an enzyme known as SidA, which is essential for the synthesis of molecules called siderophores that are made during infection to steal iron from human proteins. Furthermore, by performing high-throughput screening in the center’s Drug Discovery Screening Laboratory, they found a compound called Celastrol that blocks the growth of iron-producing organelles in the fungus. The results were published in the journal ACS Chemical Biology. “This project shows what an asset the screening lab is to the community,” said Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences and director of the screening laboratory. “Without the robots and chemical libraries available at the screening lab, this work would not have been possible. We are very fortunate at Virginia Tech to have this facility.” Aspergillus fumigatus is common and is typically found in soil and decaying organic matter. Most people are exposed to it daily with little consequence, but it can cause lung damage in people with compromised immune systems, such as organ transplant recipients and people with AIDS or leukemia. The mortality rate of this population, when exposed to the fungus, is more than 50 percent, according to the authors. "Growing antibiotic resistance is demanding the development of target-directed therapies," said Julia S. Martin del Campo, a postdoctoral research scientist in Sobrado's lab. "This approach requires the discovery of enzyme inhibitors that block essential pathogen pathways. The discovery of Celastrol as a SidA inhibitor represents the first building block in the development of drugs against A. fumigatus and related pathogens.” The Virginia Tech Center for Drug Discovery was established in 2012 and is an interdisciplinary group committed to continuing the growth and advancing the stature of the existing drug discovery and development programs at Virginia Tech. The center is housed in the College of Science, with support from the College of Science, the Fralin Life Science Institute, the Institute for Critical Technology and Applied Science, and the College of Agriculture and Life Sciences.

Zhang R.,New York University | Bloch N.,New York University | Nguyen L.A.,University of Rochester | Kim B.,Center for Drug Discovery | Landau N.R.,New York University
PLoS ONE | Year: 2014

SAMHD1 restricts the replication of HIV-1 and other retroviruses in human myeloid and resting CD4+ T cells and that is counteracted in SIV and HIV-2 by the Vpx accessory protein. The protein is a phosphohydrolase that lowers the concentration of deoxynucleoside triphosphates (dNTP), blocking reverse transcription of the viral RNA genome. Polymorphisms in the gene encoding SAMHD1 are associated with Aicardi-Goutières Syndrome, a neurological disorder characterized by increased type-I interferon production. SAMHD1 is conserved in mammals but its role in restricting virus replication and controlling interferon production in non-primate species is not well understood. We show that SAMHD1 is catalytically active and expressed at high levels in mouse spleen, lymph nodes, thymus and lung. siRNA knock-down of SAMHD1 in bone marrow-derived macrophages increased their susceptibility to HIV-1 infection. shRNA knock-down of SAMHD1 in the murine monocytic cell-line RAW264.7 increased its susceptibility to HIV-1 and murine leukemia virus and increased the levels of the dNTP pool. In addition, SAMHD1 knock-down in RAW264.7 cells induced the production of type-I interferon and several interferon-stimulated genes, modeling the situation in Aicardi-Goutières Syndrome. Our findings suggest that the role of SAMHD1 in restricting viruses is conserved in the mouse. The RAW264.7 cell-line serves as a useful tool to study the antiviral and innate immune response functions of SAMHD1. © 2014 Zhang et al.

Ryoo J.,Seoul National University | Choi J.,Seoul National University | Oh C.,Seoul National University | Kim S.,Seoul National University | And 15 more authors.
Nature Medicine | Year: 2014

The HIV-1 restriction factor SAM domain-and HD domain-containing protein 1 (SAMHD1) is proposed to inhibit HIV-1 replication by depleting the intracellular dNTP pool. However, phosphorylation of SAMHD1 regulates its ability to restrict HIV-1 without decreasing cellular dNTP levels, which is not consistent with a role for SAMHD1 dNTPase activity in HIV-1 restriction. Here, we show that SAMHD1 possesses RNase activity and that the RNase but not the dNTPase function is essential for HIV-1 restriction. By enzymatically characterizing Aicardi-Goutières syndrome (AGS)-associated SAMHD1 mutations and mutations in the allosteric dGTP-binding site of SAMHD1 for defects in RNase or dNTPase activity, we identify SAMHD1 point mutants that cause loss of one or both functions. The RNase-positive and dNTPase-negative SAMHD1 D137N mutant is able to restrict HIV-1 infection, whereas the RNase-negative and dNTPase-positive SAMHD1 Q548A mutant is defective for HIV-1 restriction. SAMHD1 associates with HIV-1 RNA and degrades it during the early phases of cell infection. SAMHD1 silencing in macrophages and CD4 + T cells from healthy donors increases HIV-1 RNA stability, rendering the cells permissive for HIV-1 infection. Furthermore, phosphorylation of SAMHD1 at T592 negatively regulates its RNase activity in cells and impedes HIV-1 restriction. Our results reveal that the RNase activity of SAMHD1 is responsible for preventing HIV-1 infection by directly degrading the HIV-1 RNA. © 2014 Nature America, Inc.

News Article | October 11, 2016

A popular antibiotic called rifampicin, used to treat tuberculosis, leprosy, and Legionnaire's disease, is becoming less effective as the bacteria that cause the diseases develop more resistance. One of the mechanisms leading to rifampicin's resistance is the action of the enzyme Rifampicin monooxygenase. Pablo Sobrado, a professor of biochemistry in the College of Agriculture and Life Sciences, and his team used a special technique called X-ray crystallography to describe the structure of this enzyme. They also reported the biochemical studies that allow them to determine the mechanisms by which the enzyme deactivates this important antibiotic. The results were published in the Journal of Biological Chemistry and PLOS One, respectively. "In collaboration with Professor Jack Tanner at the University of Missouri and his postdoc, Dr. Li-Kai Liu, we have solved the structure of the enzyme bound to the antibiotic," said Sobrado, who is affiliated with the Fralin Life Science Institute and the Virginia Tech Center for Drug Discovery. "The work by Heba, a visiting graduate student from Egypt, has provided detailed information about the mechanism of action and about the family of enzymes that this enzyme belongs to. This is all-important for drug design." Heba Adbelwahab, of Damietta, Egypt, a graduate student in Sobrado's lab, was a key player in the research and first author of the PLOS One paper. "Antibiotic resistance is one of the major problems in modern medicine," said Adbelwahab. "Our studies have shown how this enzyme deactivates rifampicin. We now have a blueprint to inhibit this enzyme and prevent antibiotic resistance." Rifampicin, also known as Rifampin, has been used to treat bacterial infections for more than 40 years. It works by preventing the bacteria from making RNA, a step necessary for growth. The enzyme, Rifampicin monooxygenase, is a flavoenzyme -- a family of enzymes that catalyze chemical reactions that are essential for microbial survival. These latest findings represent the first detailed biochemical characterization of a flavoenzyme involved in antibiotic resistance, according to the authors. Tuberculosis, leprosy, and Legionnaire's disease are infections caused by different species of bacteria. While treatable, the diseases pose a threat to children, the elderly, people in developing countries without access to adequate health care, and people with compromised immune systems.

News Article | March 3, 2017

Picking up a quest abandoned by Big Pharma, academic labs are using new technology to develop contraceptive drugs for men. Somewhere in Martin Matzuk’s collection of two billion chemicals, he hopes, is one that might safely make a man temporarily sterile—the elusive “male pill.” Right now, male contraception means a condom or a vasectomy. But Matzuk, who is director of the Center for Drug Discovery at Baylor College of Medicine, is among a handful of scientists who are renewing the search for a better option—an easy-to-take pill that’s safe, fast-acting, and reversible. Big drug companies long ago dropped out of the search for a male contraceptive able to chemically intercept millions of sperm before they reach a woman’s egg. But Matzuk’s lab shares in $600,000 worth of awards that the Bill and Melinda Gates Foundation gave out last year to “test the feasibility” of “disruptive and high-risk approaches” to male birth control. That sum is pocket change next to the $147.9 million the same foundation spent in 2015 on family planning efforts aimed at women—efforts that it says reduce poverty. Scientists like Matzuk also think excessive population growth is a cause of scarcity and environmental degradation. “We just can’t sustain the population at the rate we’re going,” he says. A male pill could reduce the number of unintended pregnancies, which by one account make up 40 percent of all pregnancies worldwide. “Right now the chemical burden for contraception relies solely on the female. That’s an unfair balance in the equation,” says Charles Easley, an assistant professor at the University of Georgia, who is also involved in the Gates-backed hunt for a male pill. “I think there’s not much activity in this field because we have an effective solution on the female side.” To restart the search for a pill, Matzuk is beginning with lists of genes active in the testes and then creating mice that lack those genes. To do that, he’s working with researchers in Japan to use the gene-editing technology called CRISPR to snip out the genes one by one. Matzuk has so far made more than 75 of these “knockout” mice and says CRISPR makes the work much faster than it would be otherwise. These mice are allowed to mate, and if their female partners don't get pregnant after three to six months, it means the gene might be a target for a contraceptive. Of 2,300 genes that are particularly active in the testes of mice, Matzuk has zeroed in on 30. His next step, he says, will be a novel screening approach to test whether any of about two billion chemicals can disable these genes in a test tube. Promising chemicals could then be fed to male mice to see if they cause infertility.

Vishnumurthy K.,Center for Drug Discovery | Makriyannis A.,Center for Drug Discovery
Journal of Combinatorial Chemistry | Year: 2010

Microwave-promoted novel and efficient one-step parallel synthesis of dibenzopyranones and heterocyclic analogues from bromo arylcarboxylates and o-hydroxyarylboronic acids via Suzuki-Miyaura cross coupling reaction is described. Spontaneous lactonization gave dibenzopyranones and heterocyclic analogues bearing electron-donating and -withdrawing groups on both aromatic rings in good to excellent yields. © 2010 American Chemical Society.

News Article | September 22, 2016

Researchers with the Virginia Tech Center for Drug Discovery have identified a compound that blocks the growth of a fungus that causes deadly lung infections and allergic reactions in people with compromised immune systems.

FALLS CHURCH, Va., Dec. 5, 2016 /PRNewswire-USNewswire/ -- Inova announced today that Milton L. Brown, MD, PhD, has joined Inova where he will serve as director of the new Inova Center for Drug Discovery and Development and as deputy director for Drug Discovery for the Inova Schar Cancer...

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