Drug design New book introduces fresh approach

first_imgLong Description ShareCONTACT: Jade BoydPHONE: 713-348-6778E-MAIL: [email protected] design: New book introduces fresh approachRice professor says drug industry can improve drug safety, lower costsThe pharmaceutical industry can reduce costs, bring new drugs to marketmore quickly and decrease the dangerous side effects of new medicationsif it pays closer attention to the latest research regarding the subtledifferences between closely related protein targets. A new book, “Transformative Concepts for Drug Design: Target Wrapping”(Springer) by Rice University bioengineering professor Ariel Fernandez,suggests new methods the industry can use to improve its bottom linetoday. The same methods could also usher in an era of personalizedmedicine by allowing drugmakers to identify idiosyncratic differencesamong individuals and to tailor drugs for patients.“Theindustry is at a crossroad,” said Fernandez, Rice’s HasselmannProfessor of Bioengineering. “The old way of finding therapeuticcompounds by trial and error is playing out. Genomics has revealed theprotein targets for many major diseases, but current methods of drugdiscovery are often hopelessly inadequate for the task of attackingthese targets.”Fernandez said it takes about a decade and costsabout $1 billion to bring a new drug to market, and the lead time andcosts for drug development are increasing.When the human genomewas sequenced a decade ago, many believed it would lead to an era of“rational” drug design in which drugmakers would create drugs moleculeby molecule. But rational drug design hasn’t panned out, largelybecause scientists still don’t understand the fundamental biophysicalprinciples that govern how drug molecules interact with proteins,Fernandez said.“Proteins come in families, and the members ofthese families, or paralogs, can be almost identical,” he said. “It isvery difficult to find a compound that will selectively target oneparalog without targeting the others.”Long DescriptionForexample, blocking the protein called “focal adhesion kinase,” or FAK,has been shown to decrease the risk of metastasis of some types ofcancer. But a standard structural analysis shows that FAK is nearlyidentical to the protein that insulin molecules use to dock with cells.Designing a drug that blocks FAK and does not block the insulinreceptor signaling on cells has proven extremely difficult.Thesimilarities between proteins that are linked with diseases and thosethat are crucial for healthy function in other parts of the body arethe underlying cause for the side effects of drugs.A crucialproof of concept for the innovative remedial approaches proposed in thebook came in 2007. Fernandez said that at that time, he and colleaguesfrom the University of Texas M.D. Anderson Cancer Center used the newmethods to re-engineer the powerful anticancer drug imatinib — bestknown by its brand name Gleevec — to more specifically target one typeof cancer while curbing a rare life-threatening cardiotoxic side effect.Theredesigned drug is identical to imatinib, save for the addition of fouratoms at a key point. Though the change is minimal, it allows the drugto effectively target cancer-related proteins without affecting similarproteins in heart cells.“Almost all proteins have minor defectsor structural deficiencies that leave some of their hydrogen bondspoorly shielded from water,” Fernandez said. “These incompletelywrapped bonds, which I termed dehydrons, differ even between closelyrelated protein paralogs, and drugmakers can use them as the basis forre-engineering drugs to be more selective.”Fernandez said manypotential drug compounds are effective disease fighters but are droppedduring late-stage trials — and at great cost — because of toxic sideeffects. Re-engineering such compounds could save drugmakers a fortunein research and development costs.“This is not a de novorational drug design,” he said of the re-engineering method. “Itextends the tried-and-true drug discovery methods industry iscomfortable with, but it does this in a rational way that will saveR&D costs, reduce toxic side effects and ultimately increase thesafety of molecular targeted therapy.” ARIELFERNANDEZ AddThislast_img

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