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Schrödinger's New Platform for Real-Time Collaboration on Drug Design


By Bio-IT World Staff 

April 4, 2014 | In the risk-averse and data-protective world of drug discovery, Schrödinger stands out as one of the earliest software providers to aggressively pursue cloud computing as a vehicle to speed up the process of finding and developing lead compounds. A longstanding partnership with Cycle Computing, building cloud networks inside Amazon Web Services, has allowed Schrödinger to run its most computationally demanding software at unprecedented speeds. In a 2012 run of the company’s Glide program, which simulates the docking of prospective drugs with their protein targets, in infrastructure provided by Cycle, Schrödinger screened 21 million compounds against a molecular target in just three hours, a feat that earned the company a Bio-IT World Best Practices Award in the category of “IT Infrastructure.” Since then, Schrödinger and Cycle have teamed up on the world’s largest cloud computing run to date, tapping into 156,000 computer cores to screen molecules for their properties as semiconductors.

Now, Schrödinger is deploying a new software solution to take advantage of the cloud as a home for collaboration. The product, LiveDesign, is the first chemical design platform to run in open, interactive sessions where participants can draw and evaluate new molecules in real time. The platform was made available on the web this Wednesday.

LiveDesign has already been used extensively in Schrödinger’s own projects. The company’s Drug Discovery Applications Group (DDAG), which partners with industry to provide chemistry services in drug development projects, now routinely turns to LiveDesign when working with distributed teams that may span continents.

“We see this over and over with our collaborators, where their teams are split among multiple states or countries, and almost all of them have interactions with CROs and need to be able to communicate effectively with them,” says Leah Frye, Vice President of the DDAG and formerly a lead chemist at pharmaceutical company Boehringer Ingelheim. “Getting the right data in front of the right people, and being able to organize it and communicate it in a fashion where you can make decisions rapidly, is a huge bottleneck.”

Compound Creation 

Computational chemistry has become a standard tool in drug design, but the ability to model chemical properties prior to synthesis comes with its own set of delays. The medicinal chemists who are most familiar with the particular hurdles of any given project, and who are responsible for working with the live compounds, can find themselves waiting on the computational chemists’ input at multiple stages of design.

Before LiveDesign, says Frye, “if you wanted to have medicinal chemists’ input at every single stage, it was really difficult… We would have a meeting to discuss the problem, and people would be rattling off ideas verbally, and trying to capture them on paper. Finally they’ll say, okay, I’ll submit [this prospective compound] to you as an SD file. Sometimes you get SD files, sometimes you get ChemDraw files. And so after the meeting’s over, the computational chemists would have to get those separate ideas together and put them in the right file format, and then run the initial calculations.” The results of those calculations would then be sent back to the medicinal chemists – who might see a promising lead to take into the lab, or might want to repeat the process with new compounds.

LiveDesign allows those calculations to be run during the meeting, with new molecules developed on the fly. During a session, all the relevant staff from partnering organizations can simultaneously log into a project’s Live Report, where the information on that project is stored. While the team members bring up problems and properties to be optimized, chemists can draw new compounds, or manipulate old ones, viewing the results in either 2D or in a 3D rendering through the popular visualization tool PyMOL.

 LiveDesign 

Two different views of a Live Report. In the foreground, a new compound under construction is rendered in PyMOL. Image credit: Schrödinger 

Live Reports are organized as spreadsheets, with each row representing a prospective compound. The columns can be filled in with chemical data imported from other databases, or discovered by experiment, but chemical properties can also be predicted using computational tools.

“You can incorporate any technology into that workflow,” says Frye. “It doesn’t have to be a Schrödinger product.” Through LiveDesign’s extensible API, any application can be made to run inside a Live Report, which will calculate values for each molecule in the spreadsheet. These tools can be used to estimate physical chemical or pharmacokinetic properties, toxicity, or specific affinity for a target molecule. When a user draws a new compound, the workflow is run automatically, returning results within seconds. If the properties look good, the user will then share the design with the rest of the team, who see it appear in the Live Report immediately.

The tools and properties in a Live Report can also be changed as a project evolves. “It’s suited for everything from hit identification, all the way through development candidates,” says Frye. “Drug discovery is an iterative process, so once you get a lead compound, you’re going to go in and try to make it more potent, and then solve all the ADME-tox issues. You need to be able to pull in the data, and share it, through the whole process.”

A Unified Platform 

The consolidation of applications means that LiveDesign is not only an environment for sharing compounds through the cloud, but also a home for project data. “One problem we’re trying to solve here is the application sprawl,” says Scott Becker, Schrödinger’s Vice President of Enterprise Products and the product manager for LiveDesign. “This is a problem with computational chemistry tools, where an end user might be dealing with six to eight different applications at any one time… You have Spotfire, you have Excel, you have your electronic lab notebook, you probably have some sort of database access tool, and scientists are spending a significant amount of time just moving data between these systems.”

For real-time collaboration, Becker and his team have taken advantage of LiveDesign’s presence in the cloud to speed up workflows. “For quick properties, we’re sub-second,” he says. “The system is set up to handle parallelization of tasks. It takes advantage of the hardware that’s available, so if the team has a cluster available, or multiple cores, that helps.” Even for more sophisticated programs, like the Glide application for 3D docking with protein targets, Becker says his goal has been to run the program in ten seconds or less.

The most complex applications still have to be run outside of LiveDesign, as computational chemists are used to working with calculations that may take days to resolve. But, says Frye, “you want to make sure you put the right [compounds] into the longer calculations.” LiveDesign helps computational and medicinal chemists quickly reach agreement on which compounds should move into these more intensive screenings, without a feedback delay on the shorter calculations.

LiveDesign can also be used to make connections across a company’s portfolio of projects. When a new compound is created, LiveDesign flags it with the name of the designer and the date. Users can later add comments to the compound, capturing data or ideas that aren’t represented elsewhere in the Live Report. This information travels with compounds through the system, so if the same molecule is considered in two separate Live Reports, members of large organizations can quickly see who else has worked with the compound and what their experience was. Schrödinger is also working with SureChem to add a similarity search feature to LiveDesign, making it possible to search for related molecules in a company’s portfolio, which other teams may already have evaluated.

Variable access settings for each Live Report help tailor the platform to the privacy needs of companies with many external partners. “We work with a lot of companies that have their synthesis, and sometimes biology, done externally through CROs,” says Frye. “When you pick the compounds that you want to put on the synthesis queue, all you have to do is move them to a Live Report that the CRO has access to.” This helps assure companies that their proprietary information stays securely in-house, while making it easy to transmit select data to partners.

“[Cloud computing] is still novel, although there are a handful of early adopter companies that are getting onto Amazon Web Services right now,” says Becker. While clients in the pharmaceutical industry have sometimes been reluctant to place their data in a remote network, Schrödinger is hopeful that the speed and collaborative capabilities of cloud computing will quickly overcome that hesitation. “The data is even more secure on the right cloud, like Amazon, where there are multiple layers of security,” says Becker. “We encrypt users’ data, and we can host it on a private instance so there’s no data in shared databases. It’s ultimately up to the comfort level of our end users.”

LiveDesign is sold independently of Schrödinger's computational software, and is designed to work with each client's preferred applications.

Editor's note: Schrödinger will be demonstrating its products on the exhibition floor at the 2014 Bio-IT World Conference & Expo, April 29 to May 1, in Boston.

 

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