Discovery studio 3

All molecular simulations were performed using Discovery Studio 3.1 (Accelrys, San Diego, CA, USA). Accelrys Discovery Studio 3.1 is available from Accelrys Inc.-San Diego, CA 92,121, USA. Protein structures were obtained from the Protein Data Bank (PDB). All protein structures were prepared before molecular docking. Active sites were defined using “From Current Selection” tools based on active residues including catalytic triad residues and oxyanion hole residues. All chemical compounds were constructed manually using Discovery Studio Visualizer and were subjected to the “Minimization” module for full structural refinement with 5000 steps of the steepest descent algorithm, followed by 2000 steps of the conjugate gradient algorithm energy minimization, utilizing the generalized born implicit solvent model and the CHARMM forcefield. Molecular docking was then performed using the “Flexible Docking” module [21] (link) implemented in Discovery Studio 3.1 [22] (link). Finally, conformations with highest -CDocker interaction energy in each docking process were analyzed and visualized in Discovery Studio (detailed in Supporting information). For the substrate binding step, -CDocker Interaction Energy (-CDIE) and -CDocker Energy (-CDE) were used to evaluate the interaction energy and enzyme-substrate complex stability, respectively.

Both ADME and TOPKAT analyses were performed using Discovery Studio^® 3.1 (Accelrys, San Diego, USA). ADME analysis was performed using six descriptors such as human intestinal absorption, aqueous solubility, blood–brain barrier, cytochrome P450 2D6, plasma protein binding, and hepatotoxicity. As for the TOPKAT analysis, five descriptors were used which includes aerobic biodegradability (AB), Ames mutagenicity, ocular irritancy, skin irritancy, and skin sensitization.