• respect at least 3 out of 4 Lipinski rules Additionally, we requested the ligand to contain only the elements C, O, N, H, S, F, Cl, and Br. Phosphorus, silicon and iodine could be allowed, while boron and selenium needed to be excluded as they are not parameterized in the MMFF-like force field used for small-molecule modeling in AC. We applied the same quality filters to all seven previously published test sets and collections of covalent complexes. The results (Table ) show that only 30 to 50% of the complexes included in previous benchmark sets pass our filters and are therefore suited for benchmarking docking algorithms. Subsequently, we identified the chemical reaction occurring between the ligand and the reactive protein side chain for each complex. Complexes for which the reaction could not be identified due to lack of information in the structure and the corresponding publication were excluded. We distinguished eight chemical reactions (Supporting Information, Figure ), namely (1) carbonyl addition, (2) nitrile addition, (3) addition on Michael acceptor, (4) nucleophilic substitution, (5) ring opening, (6) disulfide formation (Cys only), ( ) β-lactam opening (Ser only), ( ) imine formation (Lys only). Contrarily to existing benchmark sets containing only cysteines and serines, we obtained valid complexes for five reactive protein side chains, namely Cys, Ser, Lys, Asp, and Glu.