The chemical space is so vast that only a small portion of it has been examined. As a
complementary approach to systematically probe the chemical space, virtual combinatorial library
design has extended enormous impacts on generating novel and diverse structures for drug discovery.
Despite the favorable contributions, high attrition rates in drug development that mainly resulted from
lack of efficacy and side effects make it increasingly challenging to discover good chemical starting
points. In most cases, focused libraries, which are restricted to particular regions of the chemical
space, are deftly exploited to maximize hit rate and improve efficiency at the beginning of the drug
discovery and drug development pipeline. This paper presented a valid methodology for fast target-focused combinatorial
library design in both reaction-based and production-based ways with the library creating rates of approximately 70,000
molecules per second. Simple, quick and convenient operating procedures are the specific features of the method.
SHAFTS, a hybrid 3D similarity calculation software, was embedded to help refine the size of the libraries and improve
hit rates. Two target-focused (p38-focused and COX2-focused) libraries were constructed efficiently in this study. This
rapid library enumeration method is portable and applicable to any other targets for good chemical starting points
identification collaborated with either structure-based or ligand-based virtual screening.
Keywords: 3D molecular similarity, chemical space, focused library design, product-based, reaction-based, SMILES.
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