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See Inside August 2009

A Biochemical Way to Reduce Drug Side Effects?

An emerging class of medicines works its magic by targeting unusual sites on biological molecules



Slim Films

Despite what the overcrowded, overpriced shelves of your pharmacy might suggest, pharmaceutical companies struggle to find new drugs these days. The low-hanging fruit is long gone, and the main discovery method that served so well in past decades is generating far fewer hits today. But a fresh strategy, focused on a property called allosterism, is now invigorating many investigators. Some predict it will revolutionize drug discovery and could deliver treatments for diseases that so far remain intractable.

Historically, scientists have developed drugs by finding molecules that mimic the behavior of our body's signaling molecules, such as hormones and neurotransmitters. The pharmaceutical doppelgangers of such endogenous substances latch onto cell-surface receptor molecules exactly where the native substances bind. If a mimic fits snugly into the binding pocket, known as the "active" site, it will activate the receptor, triggering a biochemical cascade within the cell. If the mimic has a slightly different shape, it will do the opposite, impeding the cascade. Most drugs on the market today—allergy medicines, beta blockers, antipsychotic drugs—act in one of those ways.

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