Systematic Exploration of Binding Modes of Ligands on Drug Targets

Exploration of binding sites of ligands (drug candidates) on macromolecular targets is a central question of molecular design. Although there are experimental and theoretical methods available for the determination of atomic resolution structure of drug-target complexes, they are often limited to identify only the primary binding mode (site and conformation). Systematic exploration of multiple (allosteric or prerequisite) binding modes is a challenge for present methods. The Wrapper module of our new method, Wrap 'n' Shake, answers this challenge by a fast, computational blind docking approach. Beyond the primary (orthosteric) binding mode, Wrapper systematically produces all possible binding modes of a drug scanning the entire surface of the target. In several fast blind docking cycles, the entire surface of the target molecule is systematically wrapped in a monolayer of N ligand copies. The resulted target-ligand_N complex structure can be used as it is, or important ligand binding modes can be further distinguished in molecular dynamics shakers. Wrapper has been tested on important protein targets of drug design projects on cellular signaling and cancer. Here, we provide a practical description of the application of Wrapper.