CReM-dock: de novo design of synthetically feasible compounds guided by molecular docking

De novo generation of compounds is an attractive strategy allowing to explore much broader chemical space than virtual screening. Fragment-based approaches suffer from low synthetic accessibility of generated compounds. In this study we combined the previously developed fragment-based generator CReM and molecular docking to guide the exploration of chemical space. The developed approach is very flexible and allows to indirectly control synthetic accessibility of generated compounds, their diversity by choosing one of selection strategies, augmentation of an objective function to generate more drug-like compounds, control over preserving important protein-ligand interactions and ligand poses. The generated compounds demonstrated high novelty and were competitive to compounds generated with REINVENT4. We demonstrated in different case studies flexibility of the developed approach and its applicability to de novo generation as well as fragment expansion tasks.