NEWS OF THE WEEK
A HIT IN SILICO DRUG DISCOVERY: Computerassisted design leads to synthesis of a potent anti-HIV compound
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OMPUTER-ASSISTED DESIGN has made pos-
sible the synthesis of a reverse transcriptase inhibitor with unprecedented potency against HIV-1 activity in human T cells (J. Med. Chem., DOI: 10.1021/jm201134m). The work helps validate computational design as a route to promising drug candidates. Chemistry professor William Jorgensen and pharmacology professor Karen S. Anderson, both at Yale University, and their colleagues set out to develop a nonnucleoside reverse transcriptase inhibitor (NNRTI). This class of inhibitors binds in a side pocket of HIV’s reverse transcriptase enzyme, inhibiting motions critical in forming infective viral DNA from the virus’s genomic RNA. The group used computational design to tweak an original computer-docking hit. In vitro tests show that the com-
WILLIAM JORGENSEN
Computer model shows JLJ494 binding to a pocket in HIV-1’s reverse transcriptase.
THUMBS DOWN ON DRUG WAR WEAPON REPORT: Experts cite limitations of
Poppies grown in Afghanistan (shown) are one of the world’s largest sources of heroin. AHMAD MASSOUD/ZUMA PRESS/NEWSCOM
applying toxic fungi on illicit crops
SING FUNGAL biological agents, or mycoherbi-
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cides, would be a dubious strategy for destroying plants that produce marijuana, cocaine, and heroin, according to a National Research Council report released on Nov. 30. The agents’ efficacy is unclear, and their use would have serious limitations, say the NRC panel members. Their report examined an idea first raised in the late 1970s of developing toxic molds against cannabis, coca, and opium poppies. These crops are grown in countries including Afghanistan, Colombia, and Mexico to produce illicit drugs. Mycoherbicides have been viewed as a potentially potent weapon in the worldwide war on illicit drugs. A decade ago, for instance, the U.S. government urged Colombia to develop a mycoherbicide against coca and opium poppy plants. Fungi-based agents may be better than chemical herbicides, advocates believe, because strains could be selected to act against a specific plant species or a few closely related species, the report says. WWW.CEN-ONLINE.ORG
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pound, called JLJ494, can inhibit replication of HIV-1 in picomolar-range doses, an order of magnitude better potency than other NNRTIs. It hasn’t yet been tested in animals. Yale has filed for a patent on the compound class. JLJ494’s potential use as a drug may be limited because NNRTIs lose effectiveness quickly when HIV-1 mutates, notes Dirk Jochmans of Catholic University of Leuven, Belgium. However, the computer design was “very successful,” he says. Charles W. Flexner of Johns Hopkins University notes that five NNRTIs are already used in the U.S. and Europe. But a stronger compound requiring small doses would be easier to manufacture as well as to distribute and administer to people in poor countries. Jorgensen, Anderson, and coworkers screened more than 2 million compounds using Schrödinger’s Glide docking software. They selected nine promising candidates, three of which showed anti-HIV activity. The group then used further computations to optimize the structure of what became JLJ494, a catechol diether derivative. They suspect that JLJ494’s potency may stem from its ability to interact with a proline residue on reverse transcriptase. If true, researchers could then optimize this interaction in future designs. “I think the striking thing is that computations led us to compounds that are the most potent reported in this class,” Jorgensen says.—ELIZABETH WILSON
Others oppose these “Frankenstein fungi,” viewing them as biological or chemical warfare agents, says Sanho Tree, a fellow at the Institute for Policy Studies, a liberal think tank. There isn’t enough scientific information to determine whether mycoherbicides would effectively control illicit drug crops, the NRC report says. Conducting more research won’t guarantee the development of effective mold-based agents for this purpose, it continues. Furthermore, using mycoherbicides could harm other plants, beneficial microorganisms, or animals, the panelists warn. Plus, farmers could take counteraction after their fields have been sprayed, such as fumigating the soil to kill the fungi, they note. “The technology has some limitations,” Raghavan Charudattan, chairman of the NRC panel that produced the report, tells C&EN. For example, because their target crops are highvalue, these agents would have to be delivered at much higher risk than conventional pesticides. Growers of illicit crops would likely defend their fields by attacking the delivery aircraft, explains Charudattan, emeritus professor of plant pathology at the University of Florida. To protect the pilots, planes applying mycoherbicides would have to fly at higher altitudes than conventional crop dusters or helicopters, the report says. Use of mycoherbicides in countries where illicit drug crops are grown might be governed by the Biological Weapons Convention, it adds.—CHERYL HOGUE
DECEMBER 5, 2011
