Tag archive for pharmacology

New Research Finds Novel Uses for Old Drugs

A recent article in C&EN reports that scientists at the University of North Carolina at Chapel Hill School of Medicine and the University of California, San Francisco have developed and experimentally tested a technique to predict new target diseases for existing drugs. The team, led by Bryan L. Roth and Brian K. Shoichet, developed a computational method that compares how similar the structures of all known drugs are to the naturally occurring ligands of disease targets within cells. In their study, the scientists showed that the method predicts potential new uses as well as unexpected side effects of approved drugs.

Many of the most successful drugs on the market today are being prescribed for ailments that are quite different from the ones they were originally designed to treat since many drugs have been found to bind to multiple targets. Sometimes these interactions lead to new uses for well established drugs. At other times, they may cause harmful side effects. Either way, knowing about these interactions allows for better use of drugs.

In the new method, drug receptors are not defined by structure or sequence but by the ligands that bind to them. This approach differs from structure-based approaches which usually use a receptor’s crystal structure as a starting point.

“This approach uncovered interactions between drugs and targets that we never could have predicted simply by looking at the chemical structures,” said senior study author Bryan Roth, M.D., Ph.D., professor of pharmacology and director of the National Institute of Mental Health Psychoactive Drug Screening Program at UNC. “We may now have a way to predict what side effects are likely to occur from treatment before we even put a drug into clinical testing.” internetchemistry.com

By using a modified version of an already established algorithm used to search gene-sequence databases, compounds were screened against a database of targets, asking how much the compounds looked like the ligands. The team compared 3,665 approved or investigational drugs with hundreds of targets which were defined by their ligands. The researchers predicted thousands of unanticipated interactions and experimentally tested 30 of them. Of these 30, they confirmed 23 of the interactions.

In one case, the team found  that Rescriptor, which inhibits the enzyme HIV reverse transcriptase, also inhibited the histamine H4 receptor. The scientists have linked Rescriptor binding to histamine H4 at physiologically relevant concentrations to some of the painful side effects that the drug has. In another example, the antidepressant Prozac, whose primary target is the serotonin transporter, bound the beta-1 adrenerfic receptor, a G-protein-coupled receptor (GPCR) that usually binds such compounds as epinephrine and norepinephrine.

Roth states that the power of their approach is that it can be used to uncover the real targets of pharmaceutical compounds quickly and efficiently, and will probably lead to a greater understanding of the many molecular targets of each drug. Consequently, this new method will be an important step forward for chemists to design drugs that act on multiple targets.

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Micelles for the Delivery of Nitric Oxide

In the context of cardiovascular medicine, coronary arterial clotting from the fatty build-up from cholesterol is closely related to the control, volume, and coagulation of blood due to cells in the blood vessels. Angioplasty, the technique of mechanically widening an obstructed or dysfunctional blood vessel, is sometimes hampered by poor bodily reaction to a stent. A stent is a man-made ‘tube’ inserted into the blood vessel to prevent a localized blood flow constriction. To prevent the bodily reactions, focus has been placed on local drug delivery with inhibitors of cell growth and muscle contraction.

Nitric oxide has been shown to induce relaxation in cells of the blood vessel and regulate the strength and frequency of motion of the blood vessel muscles. Nitric oxide is difficult to deliver directly to the tissues and advancements in experimentation have been hampered by the rate at which nitric oxide releases into human tissue. Any current product has decomposed much too quickly to be useful as an effective drug. A current theory is to synthesize a molecule to bind nitric oxide to a binding molecule to slow the release of nitric oxide to the amounts needed over an extended time period. For effective treatment, nitric oxide would have to be released over a few weeks. Nitric oxide decomposes in less than fifteen seconds in blood vessel tissue, far too quickly for the treatment to be effective. It is necessary to control the release of nitric oxide into the tissues at a sufficiently slow rate while stabilizing it to last for extended periods of time, as the treatment is expensive and could be harmful with multiple doses every day. This can be achieved by attaching nitric oxide to a stable binding molecule but the size of the binding molecule needs to be sufficiently small to penetrate tissues under mild pressure.

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One of the routes taken by current research (J. Am. Chem. Soc., 2009, 131, 14413–14418) is to encapsulate nitric oxide into a complex of long carbon chains known as micelles. The micelles inhibit the release of nitric oxide by an average of over 50% compared to other molecules. Also, micelles have hydrophobic and hydrophilic properties, meaning that they can interact with solutions that are based of water, like blood, or they can penetrate into tissues with mostly cytosol, the fluid of the inside of cells. The micelle inhibits the release of nitric oxide and can be transported facilely through both blood and tissues, making it an efficient delivery pathway for the release of nitric oxide to inhibit cell growth and muscle movement in blood vessels, protecting stent operation by reducing bodily reaction to the stent.

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