Abstract
Carbonyl reductase 1 (CBR1), a short-chain dehydrogenase/reductase, is important in the phase I reduction of drugs. Glutathione (GSH) facilitates the access of low-affinity substrates to the CBR1 active site. This study investigates the path of substrates to the CBR1 active site when GSH occludes the entrance to NADP and binds its catalytic residues. A set of CBR1 structures bound with GSH were subjected to comprehensive docking and molecular dynamics (MD) simulations. The glycine moiety of GSH dangled within the active site, converting the active site into ON/OFF status, while the glutamate residue slips into a hydrophobic cavity, allowing more room for driving the substrate toward the active residues. GSH spontaneously moves within the apoCBR1 binding site and acts as an internal control barrier that selects substrates entering the catalytic site. The VAL230-TYR251 was most flexible in ApoCBR1 structure and showed a lower degree of flexibility upon the binding of inhibitors.