Computational conformational sampling is integral to small molecule 
pharmaceutical research, for detailed conformational analysis and 
high-throughput 3D library enumeration. These two regimes were tested in details 
for the general-purpose modeling program MOE, using its three conformational 
sampling methods, i.e. systematic search, stochastic search, and Conformation 
Import. The tests include i) identification of the global energy minimum, ii) 
reproduction of the bioactive conformation, iii) measures of conformational 
coverage with 3D descriptors, and iv) compute times. The bioactive conformers 
are from a new set of 256 diverse, druglike, protein-bound ligands compiled and 
analyzed with particular care. The MOE results are compared to those obtained 
from the established program Catalyst. Key parameters controlling the 
conformational coverage were varied systematically. Coverage and diversity of 
the conformational space were characterized with unique pharmacophore triplets 
or quadruplets. Overall, the protocols in both MOE and Catalyst performed well 
for their intended tasks. MOE performed at least as well as Catalyst for 
high-throughput library generation and detailed conformational modeling. This 
work provides a guide and specific recommendations regarding the usage of 
conformational sampling tools in MOE.