Sampling low energy conformations of macrocycles is challenging due to the large size of many of these molecules and the constraints imposed by the macrocycle. We present a new conformational search method (implemented in MacroModel) that uses normal-mode search steps and brief MD simulations followed by minimization. The method was parameterized using a set of 100 drug-like macrocycles from the PDB and CSD.  It was then tested on a publicly available dataset for which there are published results using alternative methods; we found that when the same force field is used (in this case MMFFs in vacuum), our method tended to identify conformations with lower energies than what the other methods identified. The performance on a new set of 50 drug-like macrocycles from the PDB and CSD was also quite good; the mean and median RMSD values for just the ring atoms was 0.60 � and 0.33 �, respectively.  However, the RMSDs for macrocycles with more than 30 ring-atoms were quite a bit larger compared to the smaller macrocycles. Possible origins for this and ideas for improving the performance on very large macrocycles will be discussed.

Macrocycle conformational sampling

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.