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Fast Track to Compounds and Crystals

By Robert M. Frederickson

Oct. 16, 2006 | Combinatorial chemistry has become a key component of early-stage small molecule drug discovery. Solid-phase combinatorial chemistry facilitates the development of compound libraries of varying size, diversity and complexity. Methods for synthesizing solid phase libraries involve synthesis of libraries of compounds in chemically inert, tagged microreactors at high efficiency.

Nexus Biosystems' IRORI systems allows synthesis of tens to tens of thousands of compounds. Nexus' Kan Reactors are miniaturized devices that contain both a functionalized solid phase support and a unique tag identifier for the synthesis of a discrete compound. Microreactors are pooled into common building block groups by a process called Directed Sorting. Synthesis takes place as reagents flow through the outer mesh walls of the microreactors. Individual reactions can be tracked with a unique laser bar code. Nexus has fully automated sorting for the synthesis, cleavage, and washing and dry-down steps.

The basic process is the same regardless of the library size-from tens of compounds to tens of thousands. Functional groups are added stepwise using standard methodology to the polymeric resin in the microreactors, followed by wash steps to remove excess reagent and reaction side products. The compound is cleaved from the support and registered on a collection plate. The AutoSort-10K executes the array defined in the database software and sorts the encoded microreactors into containers designated for each building block in the next synthesis step. The AutoWash-10K and KanWash-1K handle washing microreactors between synthesis steps.

Nexus' automation suite can be implemented as a complete package or single components can be used individually, depending on scale requirements. In-house service capabilities are also offered allowing workers to scale-up their syntheses quickly without the corresponding infrastructure and personnel requirements.

Of course, more traditional drug design based on knowledge of the structure of the drug target is alive and well, and is being used to design drugs against a myriad of new proteins identified by genomics. Nexus also offers automation tools for facilitating the growth of macromolecular crystals. Screening conditions that optimize the formation of x-ray crystallographic quality crystals can be laborious and tedious. Hundreds of conditions are typically attempted, and experiments may be monitored periodically for weeks or months.

Nexus' Crystal Farm Imaging System stores and images crystal growth in microplates in a temperature and vibration controlled environment. Images are taken over time and can

be monitored with the Crystal Navigator, a web server with 500 GB of storage that allows users to remotely schedule jobs, search the crystallization database, view and score images. Scoring requires scanning of the images to identify crystals or precipitates at each of the experimental conditions. The Crystal Resolve software package uses computer algorithms and artificial intelligence to automate the screening process.

Rare Gems
In recent years, other automated systems have been developed to lower costs and facilitate identification of appropriate conditions for crystallization of a drug target of choice. Fluidigm's Topaz system is a nanoscale chip-based device that requires much less protein and reagent per experiment than microliter-drop-based methods of crystallization. The system includes chips, reagents, hardware and software to automate nanoscale free interface diffusion, a method that samples a broader chemical space than conventional approaches.

The Topaz system for protein crystallization has recently been used in structure-based research on receptor specificity of the hemagglutinin (HA) from an H5N1 avian influenza virus, commonly known as "avian flu". The goal of the research was to identify mutations that permit influenza A viruses to cross the species barrier and adapt to a new host. The Topaz system allowed researchers to efficiently identify initial leads for solving the HA structure.

The Topaz system was also recently used by GlaxoSmithKline (GSK) solve the structure of cytochrome P450 2D6 - an enzyme important in the metabolism of a wide variety of drugs.

E-mail Robert M. Frederickson at

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