Automated flexible ligand docking method and its application for database search

✍ Scribed by Makino, Shingo; Kuntz, Irwin D.

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 305 KB
• Volume: 18
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/(sici)1096-987x(19971115)18:14<1812::aid-jcc10>3.0.co;2-h

✦ Synopsis

We have developed a new docking program that explores ligand flexibility. This program can be applied to database searches. The program is similar in concept to earlier efforts, but it has been automated and improved. The algorithm begins by selecting an anchor fragment of a ligand. This fragment is protonated, as needed, and then placed in the receptor by the DOCK algorithm, followed by minimization using a simplex method. Finally, the conformations of the remaining parts of the putative ligands are searched by a limited backtrack method and minimized to get the most stable conformation. To test the efficiency of this method, the program was used to regenerate ten ligand᎐protein complex structures. In all cases, the docked ligands basically reproduced the crystallographic binding modes. The efficiency of this method was further tested by a database search. Ten percent of molecules from the Ž . Available Chemicals Directory ACD were docked to a dihydrofolate reductase Ž . structure. Most of the top-ranking molecules 7 of the top 13 hits are dihydrofolate or methotrexate derivatives, which are known to be DHFR inhibitors, demonstrating the suitability of this program for screening molecular databases.