Dissimilar ligands bind in a similar fashion: guiding the ligand binding mode prediction

The Molecular Similarity Principle have achieved great successes in the field of drug design/discovery. Existing studies focus on similar ligands, while the behavior of dissimilar ligands remains hidden in darkness. In this study, a strategy was introduced for comparing the binding modes of ligands with different molecular structures for the first time. Our systematic analysis on a newly constructed dataset of protein-ligand complexes showed that ligands with similar structures tend to share a similar binding mode, which is consistent with the molecular similarity principle. More importantly, the results revealed that dissimilar ligands can also bind in a similar fashion. This finding would open a new avenue for rational drug design. Furthermore, a template-guided method was introduced for predicting protein-ligand complex structures. Encouragingly, even with the use of dissimilar ligands as templates, our method significantly outperformed bound docking of the molecular docking method.