Detailed, superficial approach to finding new drugs

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  • Published: Jan 15, 2010
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Detailed, superficial approach to finding new drugs

An international team has used NMR spectroscopy to study neglected regions of key cell-surface proteins. They have found that these regions undergo minute conformational changes in response to drugs, a finding that could ultimately prove useful in the design of new drugs for a range of diseases.

Brian Kobilka, Michael Bokoch, and colleagues at the Stanford University School of Medicine, and in Canada, Spain, and the elsewhere in the US, have taken the first steps towards identifying a new way to discover medicinally active compounds that may one day lead to pharmaceuticals with fewer side effects.

The team looked at a class of proteins known as G-protein-coupled receptors, or GPCRs. These are common targets of drug research with some 40 percent of all currently marketed drugs linked to GPCRs, explains Kobilka. He and his colleagues focus on a particular GPCR, so-called adrenergic receptors. These are activated by the fight or flight hormone, adrenalin, and its chemical cousin, noradrenalin. These two molecules are released by the adrenal glands, which sit on top of the kidneys, and certain nerve cells, regulating critical physiological actions by the central nervous system, heart and musculature.

As with the other GPCRs, adrenergic receptors are comprised of three regions. One is the anchor for the protein in the outer cell membrane, the second protrudes from the cell and is thus exposed to the external environment, while the remaining portion is inserted into the cell's fluid interior, the cytoplasm.

When a stimulant molecule, in natural circumstances, adrenalin and noradrenalin, interacts with the protruding portion of the GPCR, it binds tightly to the receptors active site. This binding process changes the protein's conformation on the inside of the cell, the cytoplasm-facing domain, and sets off a cascade of activity within. Other molecules besides adrenalin and noradrenalin, namely drugs and toxins can agonize or antagonize this event by latching on to the receptor. Cell-surface receptors are thus important targets for drug discovery with agonists locking the target receptor into an active or even hyperactive state while antagonists deactivate or block it.

There are nine sub-types of adrenergic receptors, which all respond to adrenalin and noradrenalin but play different roles in regulating bodily functions. For instance, the beta-2 adrenergic receptor is the chief regulator of smooth muscle, especially in relaxing air passages such as the lungs (a fight-or-flight necessity). Beta-2 agonists have thus been developed as effective drugs for treating the bronchial spasm associated with asthma. The beta-1 receptor is involved in speeding up the heartbeat and stimulating the heart to pump more blood per beat, another essential fight-or-flight response. Beta-1 antagonists, commonly known as beta-blockers, are often used to treat coronary artery disease, heart failure and arrhythmia.

Unfortunately, drugs aimed at one subtype are never 100 percent specific for that subtype and also interfere with the other sub-types, which leads to side-effects. A heart patient with asthma is caught in the middle because beta-2 agonists will ease their bronchospasm but also cause unwanted stimulation of the heart. Conversely, a beta blocker will rest their beating heart but may exacerbate their asthma.

The key to developing a new generation of more specific drugs that avoid such overlap hinges on the fact that while the various adrenergic-receptor subtypes must all respond to adrenalin and noradrenalin and so must be very similar, there have to be differences between their exposed outer domains that have evolved over millions of years. The Stanford team has homed in on this difference to help find clues as to how to make drugs that bind selectively to the extracellular section of one receptor subtype, but not to the second subtype.

They used NMR spectroscopy, with heteronuclear single-quantum coherence (HSQC) and saturation transfer differencing (STD)-filtered H-detected heteronuclear multiple-quantum coherence (HMQC) pulse sequences, to look at one specific part of the beta-2 adrenergic receptor's extracellular domain. STD-filtered HMQC improved the spectral quality at the expense of longer acquisition times, the team points out. They hoped to detect subtle changes in that area when they applied three different drugs: a beta-2 adrenergic-receptor agonist, an antagonist and a third one with a neutral effect on the receptor's activation status. Even though the drug molecules target the binding site squarely, each drug resulted in a slightly different final conformation. This suggests, Kobilka explains, that the conformational shifts of this region were coupled to those triggered by the drugs' interactions with the receptor's binding pocket.

If this coupling works in reverse, molecules that bind to the extracellular domain could conceivably modulate receptor function. Thus, the diversity of different receptors' extracellular domains could be exploited to modulate receptor activity, with high subtype selectivity. Drugs that target the GPCRs' extracellular surfaces could be used to fine-tune activity, like a volume control rather an on-off switch. "For therapy, it would be nice to control the receptor's activity in this way," adds Kobilka.



The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.



NMR finds conformation subtletiesNMR finds conformational subtleties in crystal structure (Nature)

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