The advent of focused library and virtual screening has reduced the disadvantage of combinatorial chemistry
and changed it to a realizable and cost-effective tool in drug discovery. Usually, genetic algorithms (GAs)
are used to quickly finding high-scoring molecules by sampling a small subset of the total combinatorial
space. Therefore, scoring functions play essential roles in focused library design. Reported here is our initial
attempt to establish a new approach for generating a target-focused library using the combination of the
scores of structural diversity and binding affinity with our newly improved druglikeness scoring functions.
Meanwhile, a software package, named LD1.0, was developed on the basis of the new approach. One test
on a cyclooxygenase (COX)2-focused library successfully reproduced the structures that have been
experimentally studied as COX2-selective inhibitors. Another test is on a peroxisome proliferator-activated
receptors ?-focused library design, which not only reproduces the key fragments in the approved
(thiazolidinedione) TZD drugs, but also generates some new structures that are more active than the approved
drugs or published ligands. Both of the two tests took 15% of the running time of the ordinary molecular
docking method. Thus, our new approach is an effective, reliable, and practical way for building up a properly
sized focused library with a high hit rate, novel structure, and good ADME/T profile.