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Apr 15, 2009 (Vol. 29, No. 8)

Capitalizing on Fragment-Based Discovery

Computational and Medicinal Chemists Are Joining Forces to Turn Hits into Leads

  • Structurally Related Libraries

    The fragment-based drug discovery approach of Polyphor combines screening of a general compound library and a structurally related fragment library. Daniel Obrecht, Ph.D., CSO, said, “Traditionally, one starts from fragment hits that are then optimized. Our approach takes advantage of the possibility to combine structural information from fragments and structurally-related final compounds.”

    The company’s general library consists of 140 core structures from which 600 scaffolds are derived to populate a screening library of 35,000 compounds. “An important feature is that both low and high variation substituents are kept constant throughout the scaffolds. This allows one to establish an SAR already after the primary screening.”

    Polyphor’s fragment library consists of more than 1,000 fragments with molecular weights ranging from 150–350 daltons that are derived both from the scaffolds and the substituents of the Polyphor screening library. Dr. Obrecht explained, “By screening both libraries, a more comprehensive SAR can be obtained, one which allows a more directed entry into subsequent optimization and ultimately shortens the early drug discovery process.”

  • Natural Scaffolds

    “The drug discovery world has always been looking at natural products as a valuable source of bioactive molecules,” said Dmitry Genis, Ph.D., CEO, Asinex.

    “It is remarkable to note that 33 percent of new chemical entities discovered between 1981 and 2002 are natural products (or related to them). However, natural product chemistry is challenging and biologists have to deal with complicated screening procedures.

    “Since the 1980s most pharmaceutical companies have reduced their efforts in this area, and the advent of synthetic combinatorial chemistry has further contributed to this decline.”

    Dr. Genis reported that times are changing. “The past two decades of high-throughput screening have shown that the random generation of compound libraries by a pure combinatorial chemistry approach has created millions of molecules that did not match the requirements of the drug discovery industry. Therefore, it makes sense to use natural product structures as starting points for new drug-like libraries.

    “Natural products represent an additional source of diversity that cannot be found in synthetic combinatorial libraries. Our BioCore approach is a synergic compromise that solves the problematic issues of natural products and combinatorial libraries and, at the same time, allows the unification of the positive features of these two areas.

    “BioCore is the key component of our BioDesign approach. The idea is to create compounds that contain highly privileged elements from natural products and known drugs. A BioCore is the combination of two heterocycles—one is aromatic and one is saturated, linked by a carbon-carbon spacer fragment. We strongly believe that following the BioCore framework allows chemists to create nature/lead-like scaffolds,” explained Dr. Genis.

    Although the idea of incorporating natural product elements is not novel, the company has identified what it feels are under-represented areas of chemical space and implemented those into real libraries. Dr. Genis reports that, “Based on the BioDesign approach, we offer research tools based on bio-building blocks, bio-fragments, and lead-like sets, enabling easy hit-to-lead follow-up.”

    As more medicinal and computational chemists incorporate fragment-based approaches into their discovery toolbox, the field is expected to make further progress in accelerating the pace of drug discovery.


Readers' Comments

Posted 05/27/2009 by drugs

great discovery about drugs

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