Exhaustive Conformational Sampling of Complex Fused Ring Macrocycles Using Inverse Kinematics

Natural product and synthetic macrocycles are chemically and topologically diverse. An efficient, accurate, and general method for generating macrocycle conformations would enable structure-based design of macrocycle drugs or host-guest complexes. Computational sampling also provides insight into transiently populated states, complementing crystallographic and NMR data. Here, we report a new algorithm, BRIKARD, that addresses this challenge through computational algebraic geometry and inverse kinematics together with local energy minimization. BRIKARD is demonstrated on 67 diverse macrocycles with structural data, encompassing various ring topologies. We find this approach enumerates diverse structures with macrocyclic RMSD < 1.0 Å to the experimental conformation for 85% of our data set in contrast to success rates of 67-75% with other approaches, while for the subset of 21 more challenging compounds in the data set, these rates are 57% and 10-29%, respectively. Because the algorithm can be efficiently run in parallel on many processors, exhaustive conformational sampling of complex cycles can be obtained in minutes rather than hours: with a 40 processor implementation protocol, BRIKARD samples the conformational diversity of a potential energy landscape in a median of 1.3 minutes of wallclock time, much faster than 3.1-10.3 hours necessary with current programs. By rigorously testing BRIKARD on a broad range of scaffolds with highly complex ring systems, we push the frontiers of macrocycle sampling to encompass multiring compounds, including those with more than 50 ring atoms and up to seven interlaced flexible rings.