For geometry optimizations of binding pockets as described in Sec. 5.3, the DFTB3 method within the Ams-Dftb module from the Adf 2019 package was used. The Third-Order Parametrization for Organic and Biological Systems (3ob) parameters from the corresponding Slater-Koster file were used. Dispersion interactions were taken into account with the D3BJ correction with Becke-Johnson damping . The optimization was carried out in two consecutive steps. In the first step, the coordinates corresponding to hydrogen atoms were optimized, while all other nuclear positions were kept fix. In the second step, only the nuclear coordinates corresponding to the inner pair were optimized. This procedure ensures to keep the relative arrangement of environment residues and co-factors unchanged, while the inner pair coordinates are relaxed in the presence of the surrounding pocket. Default convergence criteria were applied for the optimization of hydrogen positions, whereas "loose" criteria were used in the second step of geometry optimization.