Molecular dynamics simulation of carbonyl reductase 1 clarifies the structural switch in drug metabolism

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.

羰基还原酶1（Carbonyl reductase 1，简称CBR1）属于短链脱氢酶/还原酶家族，在药物的I相还原代谢过程中发挥关键作用。谷胱甘肽（Glutathione，简称GSH）可促进低亲和力底物结合至CBR1的活性位点。本研究探究了当GSH遮蔽NADP结合位点入口并结合其催化残基时，底物抵达CBR1活性位点的路径。本研究针对一系列结合GSH的CBR1结构开展了全面的分子对接与分子动力学（MD）模拟。结果显示，GSH的甘氨酸残基部分在活性位点内悬垂摆动，使活性位点呈现“开启/关闭”状态；而其谷氨酸残基滑入疏水空腔，为推动底物靠近催化残基腾出了更多空间。GSH可在脱辅基CBR1（apoCBR1）的结合位点内自发移动，充当筛选进入催化位点底物的内部调控屏障。在apoCBR1结构中，缬氨酸230-酪氨酸251（VAL230-TYR251）区域的柔性最高，而在结合抑制剂后该区域的柔性显著降低。