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Modeling proteins better
NOTTINGHAM, U.K.—Sygnature Discovery, an independent integrated drug discovery and preclinical services company, in mid-April announced a collaboration with SilcsBio, a scientific software company focused on high-throughput fully atomistic simulations of protein targets and protein-ligand structures, with an eye toward improving clients’ drug discovery efforts.
To that end, SilcsBio has provided Sygnature with access to its SILCS (Site Identification by Ligand Competitive Saturation) and SSFEP (Single Step Free Energy Perturbation) software, meaning that “Sygnature’s researchers are now able to offer clients the benefits of these powerful techniques in their drug discovery projects,” according to a news release about the deal.
The SILCS software identifies binding site hot spots on a protein’s surface. This could, potentially, include what Sygnature says are “cryptic pockets,” or binding sites for which little structural information is available.
SILCS methodology involves performing molecular dynamics simulations on a protein in an aqueous solution of chemically diverse small molecules. This generates probability distributions of fragment types, termed FragMaps. These FragMaps reportedly can be used rapidly and with minimal computational expense to predict or refine ligand binding poses, quantitatively score ligands in the binding pocket, and generate multiple receptor-based pharmacophore models for use in virtual screening campaigns. This has been shown to be a more effective technique than standard docking studies or receptor-based pharmacophore modeling.
Complementing this is the SSFEP software, which reportedly has demonstrated success in ranking compound binding affinities to target proteins. In particular, the SSFEP approach is said to be about a thousandfold faster than the more widely used FEP methodology. It achieves this speed by post-processing molecular dynamics simulation data of a ligand, and using it to estimate the alchemical free energy change of chemically modifying that ligand.
As Sygnature notes, “Such a rapid assessment of the drug design team’s ideas could be advantageous in speeding up the design-test-optimize cycle. Being able to evaluate and prioritize design ideas in just a few days can have a significant impact in structure-based design projects.”
Over about the past six months, Sygnature has applied the SilcsBio software suite successfully in various hit-to-lead and lead optimization projects, the company reports.
Among some of the software’s successes are that it:
“We’re delighted to be collaborating with Sygnature Discovery to bring the advantages of our drug design software to Sygnature’s projects and customers. This collaboration is very meaningful to us, as Sygnature continues to be a great partner and it opens the door to new markets for SilcsBio,” said Ken Malone, CEO of SilcsBio.
Added Bill Tatsis, a computational chemist at Sygnature Discovery: “SilcsBio software suite, with its robust physics-based algorithms and user-friendly interface, provides great leverage in the structure-based drug design area and enables us to rapidly validate new ideas/hypotheses.”
In other computational news from Sygnature recently, the company noted in March that it is taking a cue from retail stores to improve its chemical work.
As the company reports, it already had a database, run by Cambridge-based ChemInventory, that details all of Syngature’s chemicals and their locations.
“But keeping it up to date relied on us logging in to the system on a computer whenever we took or moved a chemical, taking several minutes. It was all too easy to think, ‘Oh, I’ll do it later,’ and then forget all about it, leaving the database inaccurate,” Sygnature noted. So, how to fix it? “The inspiration lay in self-scanning check-outs in the supermarket. Like groceries, bottles of chemicals have individual barcodes that identify them. Working with ChemInventory, we developed a system called ScanStation that uses these barcodes. It relies on low-cost tablet computers attached to barcode scanners. They’re always on, and are placed in strategic locations around our labs.”
So now, every time a member of the staff takes a chemical from stores or another scientist’s fume hood, they scan the barcode on their staff ID cards and then scan the barcode on the bottle.
“The ScanStation automatically updates the database with the person now responsible for the chemical. If we finish the bottle, then we scan a ‘trash’ barcode by the ScanStation followed by the bottle’s barcode. This tells the database it is empty, and it will be deleted from the system,” Sygnature explains. “This new process is so much easier. There’s no need to remove gloves to log in to the computer—just a quick zap on the scanner and it’s done. Now when we check the database for a chemical, we get an instant answer that reliably tells us whether we have any in stock, and where we will find it.”