简介：

Lead optimization is still something of an art. Structural modifications that logically should enhance affinity often decrease it. Project duration can be lengthy, the process uncertain, and progress intermittent. RACHEL™ is an application designed to streamline this laborious task.

Starting from a ligand/receptor structure, RACHEL performs automated combinatorial optimization of lead compounds by systematically derivatizing user-defined sites on the ligand. These compounds are conformationally searched within the active site, evaluated, and only those that bind tightly with the receptor are retained. This new population of compounds is then processed to form the next generation of derivatives. Over time, a lead compound is iteratively refined into a set of high affinity structures.

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RACHEL Brochure (530k)

The X-ray structure of wildtype tern N9 influenza virus neuraminidase (2QWK) shown with five ligands generated using RACHEL that are predicted to be active. Hydrogen bonds between the ligands and residues are indicated by dashed yellow lines. The surface was rendered using MOLCAD™ and color-coded according to hydrogen acceptor/donor density. Dark purple regions contain a greater acceptor/donor density and light purple regions indicate areas where hydrogen bonding is less likely to occur.

Key Benefits

• Chemical fragments are obtained directly from personal, corporate, or commercial databases increasing the likelihood of synthetically accessible results
• Building block components are selected for use based on favorable interaction with the active site
• Templates and chemical descriptors can be independently configured for each substitution site enabling complete user control of structure generation
• Focused scoring functions can be automatically generated based on user supplied structure-activity data