July 4, 2017

The Promise of Computational Drug Design

With society facing a steadily increasing burden of brain disease, researchers in the HBP are launching a collaborative initiative to identify potential new brain drugs.

The initiative will use computational drug design to search for new molecules that interact with the allosteric mechanisms of the brain, an approach that the HBP’s Dr Jean-Pierre Changeux says offers great potential.

A meeting to discuss the state of play in the field, as well as future approaches, was held in Paris on July 6, chaired by Paolo Carloni from Jülich (Germany) and Dr Changeux from Institut Pasteur (France).

“The burden of brain disease in Europe is extremely high,” says Dr Changeux, “Across 30 countries it was estimated to cost 800bn euro in 2010. So it is an enormous amount of money and the number of new drugs for brain disorders each year is unfortunately very small.”

“We consider it an ethical responsibility to engage in this area.”

A schematized pentameric receptor channel like the nicotinic receptor of acetylcholine.
The Ca++ site and the intersubunit TM site are typical allosteric sites. 

A call for collaborators in the project (officially known as Co-Design Project 6: Modelling Allosteric Drugs) was launched on July 10. Two projects will be funded and will begin next year. The search will focus on an innovative approach to drug discovery, exploring the molecular dynamics of neurotransmitter receptors and their regulation by allosteric modulators.

Dr Changeux says that the "classical" strategy of drug design is to search for compounds that are the structural analogs of neurotransmitters. Known as orthosteric ligands, these either act as an agonist, like the neurotransmitter, or as competitive antagonist interacting with the neurotransmitter (by ). In contrast, indirectly control - positively or negatively- the signal transduction process when they bind to sites topographically different from the neurotransmitter binding site through a conformational change. This approach opens up the potential for new drugs with fewer side-effects.

“That is the hope,” says Dr Changeux, “We hope it is a faster and more efficient way to find new, effective drugs.”

Dr Changeux is a pioneer in the study of allosteric mechanisms. As a PhD student he co-discovered that chemical signals regulate the biological activity of regulatory enzymes by acting at allosteric sites distinct from the biologically active sites. He went on to show that this type of regulation applies to receptor mechanisms engaged in the transmission of chemical signals in the nervous system.