ELECT++: Faster conformational search method for docking flexible molecules using molecular similarity
✍ Scribed by Makino, Shingo; Kuntz, Irwin D.
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 575 KB
- Volume
- 19
- Category
- Article
- ISSN
- 0192-8651
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✦ Synopsis
We have developed a program, ELECTqq Effective LEssening . of Conformations by Template molecules in Cqq , 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 Ž . flexibility and shape FCLUSTqq , additional reagents are generated to screen Ž . the conformational space of molecules in each cluster TEMPLATEqq . We call these representative reagents of each cluster template reagents. Template reagents and clustered reagents produce, after reaction, template molecules and Ž . clustered molecules, respectively tREACTqq . 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 Ž . searches tSEARCHqq . In our incremental search method, it is necessary to Ž . 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 FCLUSTqq clusters the primary amine reagents from the Available Chemicals Directory Ž . ACD successfully. The program tSEARCHqq was applied to dihydrofolate reductase with virtual molecules generated by tREACTqq using clustered