FLAME: A program to flexibly align molecules

Herein, we describe a method to flexibly align molecules (FLAME = FLexibly Align MolEcules). FLAME aligns two molecules by first finding maximum common pharmacophores between them using a genetic algorithm. The resulting alignments are then subjected to simultaneous optimizations of their internal energies and an alignment score. The utility of the method in pairwise alignment, multiple molecule flexible alignment, and database searching was examined. For pairwise alignment, two carboxypeptidase ligands (Protein Data Bank codes 1cbx and 3cpa), two estrogen receptor ligands (1err and 3ert), and two thrombin ligands (1dwe and 1dwd) were used as test sets. Alignments generated by FLAME starting from CONCORD structures compared very well to the X-ray structures (average root-mean-square deviation = 0.36 angstrom) even without further minimization in the presence of the protein. For multiple flexible alignments, five structurally diverse D3 receptor ligands were used as a test set. The FLAME alignment automatically identified three common pharmacophores: a base, a hydrogen-bond acceptor, and a hydrophobe/aromatic ring. The best alignment was then used to search the MDDR database. The search results were compared to the results using atom pair and Daylight fingerprint similarity. A similar database search comparison was also performed using, estrogen receptor modulators. In both cases, hits identified by FLAME were structurally more diverse compared to those from the atom pair and Daylight fingerprint methods.