Technique set to improve drug design
once applied to an enzyme that degrades anti-cancer drugs in
humans, may improve such drugs' design and effectiveness.
The discovery is set to have implications on drug design as efficacy, the power of a drug to produce the desired effect, has always been a major problem of how a drug performs in situ. Cancer drugs have especially susceptible to these enzymes which could explain their relative lack of effectiveness against tumours.
The scientists have shown that the enzyme, cytidine deaminase, which is derived from bacteria and many other sources, can be made to "fly through the vapour phase," from which solvent water is totally absent, without changing its structure.
This is important as the inhibitor molecule might be changed structurally to make it fit the enzyme more perfectly and making the action of blocking the enzyme's action in destroying anticancer drugs more effective.
The technique involved introducing the enzyme-containing solution as a fine spray into a vacuum created in a mass spectrometer in the laboratory, normal solvent molecules were completely evaporated, leaving bare, charged molecules known as ions. The protein ions were trapped in the extremely high vacuum for seconds, but in the new experiments, a single water molecule remained undisturbed.
The experiment marks the first time that scientists have detected a water molecule inside a protein molecule by mass spectrometry.
When the active site of this enzyme binds to the active site of a well-fitting inhibitor molecule, it also binds a single water molecule, which appears to be trapped in a small gap left by the inhibitor. This is evidence that the enzyme's capturing of the water molecule would evaporate instantly if it were exposed to a vacuum.
Drug design wise, the presence of the water-filled gap hints at how an inhibitor might be improved further by expanding it to fill the gap, a crucial factor when designing drugs.
Dr. Richard Wolfenden, professor of biochemistry and biophysics at the University of North Carolina (UNC) School of Medicine said: "Moreover, this specific enzyme is known to inactivate the anticancer agent cytarabine."
"That inactivation limits the effectiveness of cytarabine in cancer tissue such as in non-Hodgkins lymphoma, several forms of leukemia and other cancers. By protecting cytarabine against degradation, a powerful inhibitor of the enzyme cytidine deaminase might be used in combination with cytarabine for cancer chemotherapy."
The report on the research appears in the latest issue of the Proceedings of the National Academy of Sciences.
