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A Library Of Every Drug That Could Ever Exist

  1. Phungushead
    Billions of billions of billions of maybe-helpful molecular compounds remain to be discovered, and used for targeting a whole host of medical problems. But who has the time to conjure a novemdecillion drugs? (That number is a 1 with 60 zeroes after it.) Nobody has the tools or the treasure to do that. To help narrow things down, scientists at Duke University and the University of Pittsburgh created an imaginary library of every compound that could exist. The sections are all marked out--now chemists can get to work filling them in.

    The small molecule universe, or SMU as they call it, is the set of all feasible organic molecules below a certain weight. Small molecules can cross cell walls or bind to cells, while larger molecules above 500 Daltons are too big to be as effective. Chemists led by Duke’s David Beratan built a representative library--in some ways more like an encyclopedia--which contains representations of all those feasible molecular compounds.

    They made it using a new piece of software they called Algorithm for Chemical Space Exploration with Stochastic Search (ACSESS), which uses random statistics to search the unknown. It makes random changes to known molecules, maybe adding a nitrogen here or a carbon there. Synthetic chemists checked that the new combinations made sense, and the team used that information to further train their algorithm. Ultimately, by cataloging like with like, the team came up with 9 million examples that represent all the regions of the small-molecule universe. You can think of it like an encyclopedia of molecules grouped by type: One example could have billions of subsets.

    In this stochastic voyage, the researchers found some interesting things. First, there are apparently large gaps in the existing compound collections, which is both a result of nature’s proclivity for patterns and a result of human builders. Nature uses any available building blocks to create new compounds, while humans in the lab only have a few ingredients to work with. Second, the team found vast regions of emptiness, small molecule dark matter, where countless new compounds may fit in like unknown puzzle pieces.

    This is helpful because chemists can use it like a treasure map--they may not know what they’ll find, but the map provides some pathways to get there. “It facilitates the mining of chemical libraries that do not yet exist, providing a near-infinite source of diverse novel compounds,” the authors explain. The source code for this algorithm is available to other researchers, and the paper has been accepted for publication in the Journal of the American Chemical Society.


    Rebecca Boyle
    Image: All the Drugs A new computer program allows the mining of chemical libraries that do not yet exist, providing a near-infinite source of novel compounds that could be developed into new drugs. Virshup et al./JACS
    Popular Science


  1. Phungushead
    Scientists Map All Possible Drug-like Chemical Compounds

    [IMGL="white"]http://www.drugs-forum.com/forum/attachment.php?attachmentid=32583&stc=1&d=1367028771[/IMGL] Durham, NC - Drug developers may have a new tool to search for more effective medications and new materials.

    It's a computer algorithm that can model and catalogue the entire set of lightweight, carbon-containing molecules that chemists could feasibly create in a lab.

    The small-molecule universe has more than 10^60 (that's 1 with 60 zeroes after it) chemical structures. Duke chemist David Beratan said that many of the world's problems have molecular solutions in this chemical space, whether it’s a cure for disease or a new material to capture sunlight.

    But, he said, "The small-molecule universe is astronomical in size. When we search it for new molecular solutions, we are lost. We don't know which way to look."

    To give synthetic chemists better directions in their molecular search, Beratan and his colleagues -- Duke chemist Weitao Yang, postdoctoral associates Aaron Virshup and Julia Contreras-Garcia, and University of Pittsburgh chemist Peter Wipf -- designed a new computer algorithm to map the small-molecule universe.

    The map, developed with a National Institutes of Health P50 Center grant, tells scientists where the unexplored regions of the chemical space are and how to build structures to get there. A paper describing the algorithm and map appeared online in April in the Journal of the American Chemical Society.

    The map helps chemists because they do not yet have the tools, time or money to synthesize all 10^60 compounds in the small-molecule universe. Synthetic chemists can only make a few hundred or a few thousand molecules at a time, so they have to carefully choose which compounds to build, Beratan said.

    The scientists already have a digital library describing about a billion molecules found in the small-molecule universe, and they have synthesized about 100 million compounds over the course of human history, Beratan said. But these molecules are similar in structure and come from the same regions of the small-molecule universe.

    It's the unexplored regions that could hold molecular solutions to some of the world's most vexing challenges, Beratan said.

    To add diversity and explore new regions to the chemical space, Aaron Virshup developed a computer algorithm that built a virtual library of 9 million molecules with compounds representing every region of the small-molecule universe.

    "The idea was to start with a simple molecule and make random changes, so you add a carbon, change a double bond to a single bond, add a nitrogen. By doing that over and over again, you can get to any molecule you can think of," Virshup said.

    He programed the new algorithm to make small, random chemical changes to the structure of benzene and then to catalogue the new molecules it created based on where they fit into the map of the small-molecule universe. The challenge, Virshup said, came in identifying which new chemical compounds chemists could actually create in a lab.

    Virshup sent his early drafts of the algorithm's newly constructed molecules to synthetic chemists who scribbled on them in red ink to show whether they were synthetically unstable or unrealistic. He then turned the criticisms into rules the algorithm had to follow so it would not make those types of compounds again.

    "The rules kept us from getting lost in the chemical space," he said.

    After ten iterations, the algorithm finally produced 9 million synthesizable molecules representing every region of the small-molecule universe, and it produced a map showing the regions of the chemical space where scientists have not yet synthesized any compounds.

    "With the map, we can tell chemists, if you can synthesize a new molecule in this region of space, you have made a new type of compound," Virshup said. "It's an intellectual property issue. If you're in the blank spaces on our small molecule map, you're guaranteed to make something that isn't patented yet," he said.

    The team has made the source code for the algorithm available online. The researchers said they hope scientists will use it to immediately start mining the unexplored regions of the small molecule universe for new chemical compounds.

    The research was supported by a grant from the National Institutes of Health (P50-GM067082).

    Citation: "Stochastic voyages into uncharted chemical space produce a representative library of all possible drug-like compounds." Virshup et. al. 2013. J. Am. Chem. Soc. [Epub ahead of print].

    DOI: 10.1021/ja401184g

    April 22, 2013

    Ashley Yeager
    Image: This map shows regions of the small molecule universe that chemists have explored and the ones they haven't. Credit: Virshup et. al. JACS, 2013.
    Duke University
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