We have developed a program, ELECT++ (Effective LEssening of Conformations by Template molecules in C++), to speed up the conformational search for small flexible molecules using the similar property principle. We apply this principle to molecular shape and, importantly, to molecular flexibility. After molecules in a database are clustered according to flexibility and shape (FCLUST++), additional reagents are generated to screen the conformational space of molecules in each cluster (TEMPLATE++). We call these representative reagents of each cluster template reagents. Template reagents and clustered reagents produce, after reaction, template molecules and clustered molecules, respectively (tREACT++). The conformations of a template molecule are searched in the context of a macromolecular target. Acceptable conformational choices are then applied to all molecules in its cluster, thus effectively biasing conformational space to speed up conformational searches (tSEARCH++). In our incremental search method, it is necessary to calculate the root‐mean‐square deviations (RMSD) matrix of distances between different conformations of the same molecule to reduce the number of conformations. Instead of calculating the RMSD matrix for all molecules in a cluster, the RMSD matrix of a template molecule is chosen as a reference and applied to all the molecules in its cluster. We demonstrate that FCLUST++ clusters the primary amine reagents from the Available Chemicals Directory (ACD) successfully. The program tSEARCH++ was applied to dihydrofolate reductase with virtual molecules generated by tREACT++ using clustered primary amine reagents. The conformational search by the program tSEARCH++ was about 4.8 times faster than by SEARCH++, with an acceptable range of errors. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1834–1852, 1998