Lead optimization is perfomed on compounds that have been discovered through computational and/or assay-based lead discovery. Two primary tools exist for lead optimization: RACHEL and CHARLIE, both SYBYL modules.
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| Above: A series of images showing RACHEL optimizing an initial promising lead compound to improve the affinity for the active site. Many potential optimized leads are generated for further testing. |
RACHEL (Real-time Automated Combinatorial Heuristic Enhancement of Lead compounds)
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.
CHARLIE
CHARLIE allows the user to generate scaffolds to link separate, docked, high-affinity structures into complete compounds within the confines of the active site. CHARLIE is proficient in building bridges between structures and is useful when substructures that tightly bind different regions of the active site are present.
