Accurate and Efficient Conformer Sampling of Cyclic Drug-Like Molecules with Inverse Kinematics

Identification of all of the influential conformers of biomolecules is a crucial step in many tasks of computational biochemistry. Specifically, molecular docking, a key component of in silico drug development, requires a comprehensive set of conformations for potential candidates in order to generate the optimal ligand–receptor poses and, ultimately, find the best drug candidates. However, the presence of flexible cycles in a molecule complicates the initial search for conformers since exhaustive sampling algorithms via torsional random and systematic searches become very inefficient. The devised inverse-kinematics-based Monte Carlo with refinement (MCR) algorithm identifies independently rotatable dihedral angles in (poly)cyclic molecules and uses them to perform global conformational sampling, outperforming popular alternatives (MacroModel, CREST, and RDKit) in terms of speed and diversity of the resulting conformer ensembles. Moreover, MCR quickly and accurately recovers naturally occurring macrocycle conformations for most of the considered molecules.