All in One: Cavity Detection, Druggability Estimate, Cavity-Based Pharmacophore Perception, and Virtual Screening.

Discovering the very first ligands of pharmacologically important targets in a fast and cost-efficient manner is an important issue in drug discovery. In the absence of structural information on either endogenous or synthetic ligands, computational chemists classically identify the very first hits by docking compound libraries to a binding site of interest, with well-known biases arising from the usage of scoring functions. We herewith propose a novel computational method tailored to ligand-free protein structures and consisting in the generation of simple cavity-based pharmacophores to which potential ligands could be aligned by the use of a smooth Gaussian function. The method, embedded in the IChem toolkit, automatically detects ligand-binding cavities, then predicts their structural druggability, and last creates a structure-based pharmacophore for predicted druggable binding sites. A companion tool (Shaper2) was designed to align ligands to cavity-derived pharmacophoric features. The proposed method is as efficient as state-of-the-art virtual screening methods (ROCS, Surflex-Dock) in both posing and virtual screening challenges. Interestingly, IChem-Shaper2 is clearly orthogonal to these latter methods in retrieving unique chemotypes from high-throughput virtual screening data.