Parke-Davis

 

Parke-Davis Pharmaceuticals Sees the

Future with CrystalEyes from Stereographics

 

It is no accident that medical research is yielding more dramatic results than ever in the number and efficacy of new drugs.  Researchers use molecular modeling to create, modify, study, and test interactions between molecules to design these new drugs.  Graphically intensive, successful molecular modeling depends on accurate visualization.  It is this visualization that challenges chemists as they attempt to avoid the all-too-familiar trial and error scenario of drug design.

"With CrystalEyes we've gained an understanding of the forces and factors involved in making a compound a potent drug.  Before using this equipment, we didn't fully appreciate the role that the properties play," said Dan Ortwine, a Research Associate at the Parke-Davis Research division of Warner-Lambert Company.

Parke-Davis, a division of Warner-Lambert Company, is devoted to discovering, developing, manufacturing, and marketing quality pharmaceutical products.  Its central research focus is on heart disease, diabetes, anti-infectives, central nervous system, and women's healthcare. 

Warner-Lambert Company is a worldwide company employing approximately 38,000 people, and along with Parke-Davis,  is headquartered in Morris Plains, New Jersey.  Warner-Lambert achieved sales of more than $7 billion in 1996, and will invest more than $600 million worldwide in research and development in 1997.

In the course of developing these treatments, visualizing the complex interaction of drug and biological molecules is an absolute necessity.  In the past, tinker-toy models and crude wireframe computer drawings had to suffice for the process. 

Today however, high-speed workstations, advanced modeling software and the precision 3D visiualization capabilities of StereoGraphics CrystalEyes put scientists generations ahead.  This combination allows them to work with near-exact visual replicas of complex molecules in true stereoscopic 3D, creating new possibilities never before imagined.

The Challenge:

At Parke-Davis, 15 computational chemists and structural biologists study both drug molecules and bio-molecules.  These include the body’s proteins, enzymes, or DNA with which drug molecules react. Since drug molecules are very small, typically containing 20-100 atoms, they are relatively easy to visualize.  Large bio-molecules, however, contain up to 10,000 atoms. 

To further complicate matters, molecules are not smooth.  Their topography includes nooks, crannies, bumps, canyons and holes that wire-frame or tinker toy representations cannot adequately express.

Cavities or clefts of enzymes, proteins, or DNA are the actual sites where scientists dock drug molecules and study the interaction.  Over the years, a major obstacle for Parke-Davis researchers in the drug design process was to see this interactionand see it in a useful manner.  In order to begin to understand the interaction between these molecules, it is necessary to create a three-dimensional representation.

The three-dimensional representation is created as follows:  A crystal of molecules is first bombarded with high energy x-rays creating scatter patterns.  Photomultiplier tubes electronically deliver this pattern to a workstation monitor where the x-ray scatter pattern is back-calculated, establishing the position of atoms within the molecule. 

A scientist is then able to receive a 3D view of the packing pattern of the atoms, and how the molecules arrange themselves within the crystal. Without the combination of depth cueing and stereo 3D, however, the interactions between the molecules being designed and the target enzyme, protein, or DNA would be too complex to visualize.

Two incremental technological advances occurred  to remove the barriers of seeing molecules as they really are.  The first was a major advance in three-dimensional technology that provided both depth and stereo capabilities from StereoGraphics.  The second was the delivery of adequate workstation horsepower from Silicon Graphics to enable solid modeling that made 3D come alive.

The Magic Bus:

“Our current 3D solution actually arrived on four wheels,” said Ortwine.  “Silicon Graphics’ Magic Bus, a motorhome complete with SGI’s latest workstations set up demonstrations in a parking lot at the University of Michigan, near our Parke-Davis’ facilities. That was my first glimpse of StereoGraphics’ CrystalEyes. Seeing it for the first time was startlingit just blew you away it was so far in advance of anything we had seen.  And, the feeling hasn’t changed since the first encounter,” said Ortwine.

Stereoscopic Viewing - How CrystalEyes  works:

The effect of three-dimensionality is a combination of what the human eye sees and the brain process.  The distance between human eyes results in each eye seeing an image from a slightly different perspective.  The brain combines data from the two images into a single image with depthan effect known as stereopsis.

Just as humans perceive depth and perspective stereoscopically, CrystalEyes relies on the same principle.  CrystalEyes works with the user’s computer display and software to transmit separate left eye/right eye images, creating the illusion that on-screen objects have depth and presence. 

The eyewear’s crystal shutter lenses alternately block out the wrong image and transmit the correct one, creating a realistic 3D effect.  An emitter transmits synchronized pulses of infrared signals that are received by CrystalEyes eyewear.  In effect, CrystalEyes eyewear produces stereopsis by electronically replicating the way people view their surroundings in the real worlddelivering crisp stereo 3D images without ghosting or double image artifacts.

Alternately displaying left- and right-eye perspectives on a monitor using a standard bandwidth solves a major problem of the pasttrue control of the Z-axis.  For remote manipulation and viewing of objects, stereo 3D gives the user control, along all axes including the z-axis, or depth, of changes made to a structure on the screen. 

This control is essential for exacting real-time processes such as the docking procedure critical to molecular modeling.

Solid Modeling Catches Up:

The quality of the images on workstations has improved to the point that 3D solid modeling has become a reality.  In conjunction with StereoGraphics CrystalEyes, drug design group at the Parke-Davis research facility uses 21 Silicon Graphics workstations.  These range from standard Indigo systems to a high-powered, 8-processor R10000 Infinite Reality ONYX machine. 

In addition, the researchers use a variety of molecular modeling software packages which include Sybyl from Tripos Inc. and MSI’s Quanta and Xplor products.

With these tools and CrystalEyes, the Parke-Davis researchers were finally able to put a surface on the nooks, crannies, bumps, canyons and holes that created so much confusion in the pastgiving the molecule’s topography unprecedented clarity.

Scientists added translucent, transparent or opaque surfaces.  They painted colors indicating specific electrical properties, or other types of properties, that would conform to the shape of the molecule in 3 dimensions.  They rotated molecules, studying them at different angles, and did all of these things in real time.  With CrystalEyes, the surfaces were not only visible, but also breathtaking.

Interacting with Molecules:

When the technology advances came to fruition, Parke-Davis researchers put surfaces on their molecules, and built a room where all could see them.  Modeled after a graphics visualization room at a San Diego Supercomputer Center, Parke-Davis created a similar room in late 1992built specifically to capitalize on CrystalEyes’ capabilities. Within the 20’ x 40’ room, scientific presentations take place to up to 30 scientists, and enough eyewear is available for all to view the presentation.

Four ceiling-mounted emitters ensure that no matter where anyone wearing eyewear is in the room, the infrared signal is available.  A high-powered NEC NCXG135 three-tube CRT video projection system projects vivid stereo images onto a large, 6’ x 8’ screen. 

Because the CrystalEyes glasses synchronize with 3D stereo images by the infrared emitters, any number of users can simultaneously view the display with complete freedom of movement.  Onscreen images, with realistic depth and perspective, appear to be floating off-screen and occupying space in the users’ physical environment. 

Parke-Davis scientists consider the brainstorm sessions that take place in the conference room an extremely important tool.  For evaluating or interpreting multidimensional or visually-oriented data, it allows them to make better analysis of the data, and faster analysis as well.

Injecting Rationality Into Designing Drugs:

The researchers’ mission at Parke-Davis is not necessarily to design the next billion dollar drug, but to scientifically understand a problem that’s proved intractable; assist in the drug design process; and steer research in the right direction. 

Visualizing in three dimensions allows for a substantial increase in efficiency.  For example, instead of making 200 molecules to find the best one, researchers may only create 50, and reject the remainder with greater speed and certainty.

“What we have been able to do is to inject rationality into the drug design process.  Where before it was hit and missnow we can predict before hand the potential success or failure of a change.  We’ll know in advance that a situation won’t work because a drug molecule doesn’t fit into a cavity.  That type of prediction used to be impossible.  Today we can reject much more and head directly to what we know is true,” Says Ortwine.

By making a 3-D presentation, chemists can think about chemistry while looking at how the molecules might fit into a canyon or cavitya tremendously useful process. 

As researchers mull over how to change a molecule to fit better, actually viewing the fit, a high level of give and takeexchange of ideas consistently happens.  It elevates the process of drug design to an infinitely more efficient science than ever possible before.

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