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Large Molecule Library Enables On-Demand Drug Discovery

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(xresch, Pixabay)

7 Feb. 2019. A large-scale public drug molecule library is shown with computational modeling to accurately identify on-demand new compounds that bind completely to therapy targets. A team from University of California in San Francisco, University of North Carolina in Chapel Hill, and the medicinal chemistry company Enamine Ltd. in Kiev, Ukraine, with colleagues from labs in China and Latvia, published their findings in yesterday’s issue of the journal Nature (paid subscription required).

Researchers led by UC San Francisco pharmaceutical chemistry faculty Brian Shoichet and John Irwin, and UNC Chapel Hill pharmacology professor Bryan Roth, are seeking complete yet accessible sources of chemical molecules that can be analyzed and modeled with computational techniques against treatment targets. The authors say that up to now, public chemical molecule databases are limited in the number of entries or properties used to describe those entries.

The international team is particularly interested in the capability of drug molecules to dock or bind securely in three dimensions to biological therapy targets. Shoichet and Irwin established a public drug molecule database in 2005 known as ZINC that compiles chemical structures and properties in a standard format suitable for computational analysis and screening. A key interest of ZINC is binding properties to targets that make docking possible with proteins. In this case, size matters, with the larger the collection of molecules available, say the authors, the less likely the screening will return decoy, or biologically inactive, molecules.

Several commercial sources of drug molecules offer their collections to ZINC, but the contributions from Enamine Ltd., say the authors, are particularly important. Enamine provides customized synthetic drug compounds on demand, by screening its molecular library against customer treatment targets for discovering and producing new compounds that meet customer specifications. The company says over the past 10 years it discovered more than 1 billion compounds for customers with this process. At the time of publication, ZINC amassed 170 million chemical molecules, with the number of entries now at 750 million and expected to reach 1 billion by January 2020.

“Our platform can now screen 100 times more molecules than are available in most drug screening libraries, with far more diversity in the molecules screened. Soon it will be able to screen 1,000 times more,” says Irwin in a UC San Francisco statement. “People are going to have access to a lot of new chemistry that no one has looked at before.”

The researchers tested the ability of ZINC to screen for and identify the best docking molecules against 2 widely different treatment targets. The system screened its entries for activity against the AmpC beta-lactamase enzyme associated with bacterial resistance to antibiotics and D4 dopamine receptor, associated with a number of psychiatric disorders and addictive behavior. Screening and computational analysis with ZINC returned 44 compounds docking to AmpC beta-lactamase and 549 compounds docking to D4 dopamine receptors. Among the compounds identified were an entire class of AmpC beta-lactamase inhibitors that were previously not associated with this enzyme.

The identified compounds produced by Enamine were tested in lab cultures confirmed the compounds’ docking properties from the ZINC simulations. Among the new compounds tested, say the authors, are among the most powerful inhibitors of AmpC beta-lactamase and dopamine receptor agonists discovered.

“The D4-binding compounds identified from ZINC are among the most potent ever reported,” notes Roth. “This kind of rapid screening of millions of potential compounds is a major step toward creating better medications for many illnesses, and in the case of the D4 receptor, psychiatric conditions.”

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