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Researchers at North Carolina State University have created the largest virtual library of publicly available macrolide scaffolds. The library – called V1M – contains chemical structures and properties calculated for 1 million macrolide scaffolds that can be used as antibiotics or anticancer drugs.
"As chemists, we can only examine a tiny portion of the current chemical universe," says Denis Fourches, an assistant professor of chemistry at NC State and a corresponding author of an article describing the work . "If we tried to synthesize and test all the chemicals of interest, it would take too much time and cost too much. So we have to use computers to explore these unknown parts of the chemical space. "
Chemists use computers by listing or virtually generating new molecules and comparing their predicted properties with those of existing drugs. This in silico screening method quickly and inexpensively identifies the compounds with the desired properties that experimental chemists can then synthesize and test.
Macrolides are a family of chemicals mainly used as antibiotics and anticancer drugs. Their unique cyclic structure allows them to bind to difficult protein targets. Some of them are considered last-resort medicines, especially for drug-resistant bacteria.
"Macrolides are natural products," says Fourches. "These chemicals are produced by bacteria to kill other bacteria, but the synthesis of these highly complex compounds takes 20 to 25 chemical steps, which is a long and costly process." If you want to find new compounds , simulation is by far the fastest way to do it. "
Forks and his colleagues created a computer program called PKS Enumerator, which generates very large libraries of virtual chemical analogues of macrolide drugs. The software uses chemical building blocks extracted from a set of 18 known bioactive macrolides, breaking them down into its chemical components, then rearranging them to create new compounds based on a series of rules and constraints imposed on the user. The resulting library of new macrolides – V1M – classifies new compounds by size, weight, topology, and donors and acceptors of hydrogen bonds.
"We wanted to create a virtual library of completely new chemicals that no one probably had ever synthesized, but these compounds still needed to be sufficiently similar to the known macrolide drugs to make this library relevant to the research community," says Fourches. "V1M is the first public domain library of these new macrolides, all of which are chemically similar to the 18 known bioactive macrolides we have analyzed, so hopefully other researchers will be able to use this library to better screen and identify some compounds that may be useful for drug discovery. "
The search appears in the Journal of Cheminformatics. Phyo Phyo Kyaw Zin, a graduate student from the State of NC State, is the first author. Gavin Williams, an associate professor of chemistry at NC State, also contributed to the work.
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Material provided by North Carolina State University. Note: Content can be changed for style and length.
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