High-Quality Conformer Generation with CDPKit/CONFORT: Algorithm and Performance Assessment

The majority of compounds in the drug-like chemical space show flexibility regarding their three-dimensional structure which, in solution, results in an equilibrium of multiple interconvertible conformational states. Knowledge of the putative bound-state conformation of a molecule is an essential prerequisite for the successful application of many computer-aided drug design methods that aim to assess or predict its capability to bind to a particular target receptor of interest. An established approach to predict bioactive conformers in the absence of receptor structure information is to sample the low-energy conformational space of the investigated molecules and derive representative conformer ensembles which can then be expected to comprise members that closely resemble possible bound-state ligand conformations. The high relevance of such conformer generation functionality led to the development of a wide panel of dedicated commercial and open-source software tools throughout the last decades. Several published benchmarking studies have shown that open-source tools lag behind their commercial competitors in many key aspects like accuracy in reproducing bioactive conformations, speed of processing, output ensemble size, range of applicability, stability and user-friendliness.

In this work, we introduce the novel open-source conformer ensemble generator CONFORT, which builds upon proven concepts and algorithms and aims at delivering state-of-the-art performance for all types of organic molecules in the drug-like chemical space. The ability of CONFORT, and several well-known commercial and open-source conformer ensemble generators, to reproduce experimental 3D structures as well as their computational efficiency and robustness has been assessed thoroughly both for typical drug-like molecules and macrocyclic structures. For small molecules, CONFORT outperforms all other tested open-source conformer generators and is head-to-head with commercial generators, both in terms of processing speed and accuracy in the reproduction of bioactive conformations. In the case of macrocyclic structures, CONFORT is able to reproduce experimental 3D structures with clearly higher accuracy than all other tested generators. To our knowledge, CONFORT is the first open-source conformer ensemble generator that is able to truly keep up with commercial software in this field and thus represents a valuable addition to the open-source software toolbox for computer-aided drug design.