How to build an Alzheimer drug molecule

Donald Weaver

Dr. Donald Weaver, Director at the Toronto Western Research Institute (Photo: UHN Research Communications)

Wanted: Small molecule that mixes well with water and fat. Must be exactly the right size and shape to lock onto beta-amyloid molecules in the brain and stop them from forming toxic clumps.

This molecule is a bit of a holy grail in the world of Alzheimer's drug research because it has great potential for stopping beta-amyloid from building up and killing brain cells.

The problem is, that even if this molecule already exists, researchers have not found it. If it can be synthesized, they need to figure out how. But Donald Weaver, director at Toronto Western Research Institute, is optimistic that there will be a breakthrough.

"Our lab is just one of many, many labs around the world trying to come up with drugs for Alzheimer's disease. Sooner or later, one of these labs is going to get it right," he says.

With help from the Alzheimer Society Research Program, Dr. Weaver runs a lab that specializes in computer-aided design and development of molecule-based Alzheimer drugs. He and his team use computers to map the three-dimensional shape and size of beta-amyloid's receptors. Receptors are structures on the surface of a molecule that bind with other molecules.

Knowing the receptor's size and shape allows him to search for, or synthesize, molecules that bind to it, which would make it impossible for beta-amyloid to clump together into its toxic form.

But these drug molecules must first find their way past the body's protective blood-brain barrier. Hence the need for them to mix with both water and fat. The barrier is formidable in part because our blood is water-based, while our brain is fat-based. Most molecules are soluble in one or the other.

"You need to incorporate this careful balance," says Dr. Weaver. "The molecule has to have some solubility in blood and some in the brain. Then it can cross the barrier through passive diffusion."

His lab is currently testing three promising molecules while continuing work on several others.

"We’re all looking for the next generation of compounds for Alzheimer's disease and I hope it comes out of our lab, but it will come," says Dr. Weaver.

Last Updated: 11/08/2017