ELECT plus plus: Faster conformational search method for docking flexible molecules using molecular similarity

摘要

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 (tREACT + +). 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. (C) 1998 John Wiley & Sons, Inc. [References: 34]