Vertex Pharmaceuticals

Two Problems. One Solution.

By Tim McIntire

Marc Jacobs studying X-ray crystallography on his iMac. Here, he is working with Coot (Crystallographic Object Oriented Toolkit), which is designed to work on any UNIX-based operating system and excels in a Mac OS X environment.

Vertex Pharmaceuticals Incorporated uses Macs to discover small molecules that solve big problems. Often aligning with other major pharmaceutical companies such as GlaxoSmithKline and Johnson & Johnson to commercialize their products, Vertex has produced breakthroughs that include treatments for HIV and Hepatitis C. Because their work is so graphically intensive, they needed a powerful UNIX-based system that excelled as a visualization platform to replace its aging SGI workstations. Vertex found Macs to be the optimal solution, having already used them for productivity applications. By adopting Macs for their research, they could streamline their workflow by unifying all of their tasks on a single platform.

Discovering a New Solution

Vertex Pharmaceuticals recently completed the transition to dual-processor Power Mac G5s for scientific computing. Vertex needed to replace its SGI systems when Silicon Graphics announced the discontinuation of the MIPS/IRIX product line. Critical software that was once well supported on the platform would no longer be available or further developed in the coming years. But support for science and visualization applications on Mac OS X, such as Coot and PyMOL, would continue to grow.

“I would definitely recommend Mac. We really gain as an organization from having a single system that runs Microsoft Office products on a UNIX-based desktop.”

Every member of the Vertex Structural Biology Group — from accounting to IT to research — immediately felt the benefits of doing the majority of his or her work on a single platform. Marc Jacobs, Ph.D., associate director of Vertex’s Structural Biology Group, explains: “I would definitely recommend the Mac. We really gain as an organization from having a single system that runs Microsoft Office products on a UNIX-based desktop capable of cross-mounting Linux directories and running scientific software using either a UNIX prompt or X Windows.”

Vertex personnel enthusiastically supported the move to Mac OS X because it fits the needs of all types of users. Jacobs says, “Among groups that use UNIX and Linux, the move generated a lot of excitement — and the groups who don’t use UNIX never even know there is UNIX underneath the hood.”

Removing the older SGI machines has helped the bottom line too. “The cost of updating our SGI workstations would have been very expensive and the specialized support was very expensive,” Jacobs says.

Drug discovery is a long, iterative process that typically starts with a target protein or receptor and tens of thousands of small molecules that have been selected as possible inhibitors. Vertex scientists select molecular targets associated with life-threatening or life-altering problems. If they can stop the target protein or receptor from functioning, they may have found a cure or a solution. After running through a screening process to generate a subset of small molecules that inhibit the target enzyme, Vertex’s Structural Biology Group examines these initial hits in detail.

“From the list of molecules that inhibit the enzyme, we make small, or sometimes large, changes in order to improve them,” says Jacobs. “Imagine a molecule that you know inhibits an enzyme and you want to improve it. You could start changing things in the molecule by trial and error — almost like having a key that fits in a lock but doesn’t work — you could just start moving teeth around until, eventually, you might have a key that fits properly.”

X-ray crystallography is a more systematic approach. “In X-ray crystallography we will solve a structure so we know the location of every atom of the protein and every atom in the small molecule with the drug candidate actually bound to the enzyme,” Jacobs explains. “It’s almost like looking in the inside of the lock — like x-raying the lock.”

Molecular Modeling in Mac OS X

The x-ray crystallography process is what allows scientists to see “inside of the lock.” Without the right software and stable high-performance hardware, Jacob’s group would have a difficult time doing their jobs. Mac OS X runs the majority of science software used in drug discovery, including Vertex’s software stack, which is a mix of commercial applications, open source applications, and in-house tools. Two of their applications (QUANTA and CNX) run on a Linux cluster but can be seamlessly accessed from Mac OS X desktops using Terminal or X Windows.

Cory Farinella, senior desktop support coordinator at Vertex, sees Mac Pros as the next step in Vertex’s roadmap: “The crystallography group is really excited about the Mac Pros, because of the price-performance benefits. When they upgrade, there might not even be a need for the Linux cluster since you can get a machine with a quad processor and 16GB of RAM — our modeling and 3D work require a lot of RAM for the high-end graphics.”

“Our computers have software packages that analyze X-ray scattering data and quantify the results,” Jacobs says. “We use HKL and d*TREK to take the diffraction images that are collected on the X-ray detector, quantify them, then do a Fourier transform, which relates the scattered x-rays to the structure. Then we use CCP4 and CNX to create a mathematical map that tells us where the atoms in the molecule and the chemical bonds between the atoms must be — much like the location of roads and buildings. QUANTA or Coot is used to actually construct the molecular model from the map.”

The team then comes up with ideas for a new series of compounds to run a second round of tests. This process continues iteratively until a series of criteria are met — after which in vivo testing begins.

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