Studying how long a drug stays bound to a receptor can help scientists develop more effective medicines.
One of the best-selling antihypertensive drugs candesartan lowers blood pressure more effectively than any other drug in its class. One possible reason for this effectiveness is its binding kinetics: the active agent spends several hours bound to its target receptor, the angiotensin II receptor, compared with just a few minutes for losartan — another drug in its class.
“It has been postulated that for this reason candesartan is advantageous because it produces more prolonged blood pressure lowering, meaning that it has greater efficacy at lower doses and retains efficacy in the event of a missed dose,” explains Mike Waring, principal scientist at AstraZeneca, which markets the drug as Atacand.
Over the past five years, scientists have increasingly been studying drugs’ binding kinetics, which determine how fast a drug and its receptor associate (K on ) and dissociate (K off ). There is mounting evidence to suggest that the ‘residence time’ — a term introduced by Robert Copeland and colleagues at GlaxoSmithKline in 2006 to describe the time a drug remains bound to its target — has a strong influence on a drug’s clinical success.
Only 10% of drug candidates that enter phase I trials end up being approved by the US Food and Drug Administration[1] . To try to reduce this attrition, pharmaceutical companies have started studying binding kinetics in drug discovery programmes, but this is not yet being systematically applied because of a lack of experience and uncertainty about its importance.
“Until recently, binding kinetics has been ignored — the least we can do is pay more attention to it,” says Ad IJzerman, a medicinal chemist at the University of Leiden in the Netherlands. “We want to convince the research community you can’t live without it.”
Molecular basis
The concept of binding kinetics dates back to work in the early 1960s by William Paton, one of the pioneers of pharmacology [2[9]] [3] . In one paper, Paton postulated a rate theory, which uses the interaction of a drug with its receptor to explain drug action, potency and speed of offset3 .
Several important advances have since led to the current interest. In 1984, Motulsky and Mahan laid the theoretical foundations for binding kinetics and outlined the equations used to measure it[4] . And in 2004, David Swinney highlighted the importance of the biochemical mechanism of drug action in drug efficacy and safety[5] .He described the potential discovery and development risks associated with the binding mechanism of drugs and proposed simple rules to minimise them.
However, researchers have tended to focus on the strength of the binding between a drug candidate and its target (the affinity), rather than on how long the drug remains bound to the target (the residence time). The affinity of a drug is the concentration at which 50% of the target receptors are occupied. This is the ratio of K off to K on but says nothing about the binding kinetics.
“Initially, researchers believed that if a drug has good affinity, it would have a good effect. But this is not the case,” says IJzerman. “You can have a good website, but if you don’t stick to its pages long enough, you probably won’t have learnt that much.”
He explains that two drugs can have the same affinity to a receptor but have different binding kinetics, and these may affect the drug’s efficacy. “If you focus on affinity alone, you’d have difficulty in selecting promising drug candidates,” he says.
Four key factors are thought to play a part in controlling drug–receptor binding kinetics at a molecular level: molecular size, hydrophobic effects, electrostatic interactions, and conformational fluctuations[6] .
“It has been observed that as you increase the hydrophobicity of a drug, it creates a higher energy barrier; in other words, it makes it harder for the drug to dissociate from its receptor,” says Waring. “The hydrophobic parts of a drug are shielding the hydrogen bond from the water.” He adds that the conformational flexibility of a drug is also being studied to see how it affects the binding kinetics. In general, more flexible compounds tend to have longer residence times at the target receptor.
Originally Posted by inbrugge
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