Generative Topographic Mapping of the Docking Conformational Space.

Following previous efforts to render the Conformational Space (CS) of flexible compounds by Generative Topographic Mapping (GTM), this polyvalent mapping technique is here adapted to the docking problem. Contact fingerprints (CF) characterize ligands from the perspective of the binding site by monitoring protein atoms that are "touched" by those of the ligand. A "Contact" (CF) map was built by GTM-driven dimensionality reduction of the CF vector space. Alternatively, a "Hybrid" (Hy) map used a composite descriptor of CFs concatenated with ligand fragment descriptors. These maps indirectly represent the active site and integrate the binding information of multiple ligands. The concept is illustrated by a docking study into the ATP-binding site of CDK2, using the S4MPLE program to generate thousands of poses for each ligand. Both maps were challenged to (1) Discriminate native from non-native ligand poses, e.g., create RMSD-landscapes "colored" by the conformer ensemble of ligands of known binding modes in order to highlight "native" map zones (poses with RMSD to PDB structures < 2Å). Then, projection of poses of other ligands on such landscapes might serve to predict those falling in native zones as being well-docked. (2) Distinguish ligands-characterized by their ensemble of conformers-by their potency, e.g., testing the hypotheses whether zones privileged by potent binders are clearly separated from the ones preferred by decoys on the maps. Hybrid maps were better in both challenges and outperformed the classical energy and individual contact satisfaction scores in discriminating ligands by potency. Moreover, the intuitive visualization and analysis of docking CS may, as already mentioned, have several applications-from highlighting of key contacts to monitoring docking calculation convergence.