Substructural dynamics of the phase-I drug metabolizing enzyme, carbonyl reductase 1, in response to various substrate and inhibitor configurations

Purpose: To investigate the substructure and molecular dynamics change in the phase-I drug metabolizing enzyme, carbonyl reductase 1 (CBR1), in response to different substrate and inhibitor configurations, using a molecular dynamics approach. Methods: CBR1 structure and drug ligands, including 2,3-butanedione, prostaglandin E2 (PGE2), oracine, mitoxantrone, menadione, rutoside, barbital, and biochanin A, were retrieved and 3D optimized. Docking runs were performed using template docking into CBR1 active binding site with GSH. Molecular dynamic (MD) simulation was implemented for 100 ns. Results: The docking scores were positively correlated with the detected ligand's affinities. Molecular dynamics simulation indicated that lower affinity ligands or weaker inhibitors produced less stable CBR1 with higher root mean square deviations (RMSD) of CBR1 backbone alpha-carbon atoms. Stronger inhibitors and substrates produced stable CBR1 structures with RMSD similar to or lower than CBR1-NADP complexes. Very low affinity ligands were unstable and were released from their sites within a few nanoseconds after commencing the simulation. Two flexible loops, LE92-PHE102 and VAL230-TYR251, were highly responsive to the nature of CBR1 ligands. Changes in the latter may be associated with lower CBR1 activity due to loss of stabilization of NADPH by the deviation of this loop's residues. Conclusion: In this work, a model of CBR1 structural changes has been provided that can be used in the analysis of CBR1 future substrates and inhibitors. Docking followed by MD simulation and analysis of average backbone alpha-carbon RMSD and changes in ILE92-PHE102 and VAL230-TYR251 loops can be used in the model analysis of unknown or new drug candidates to predict their binding efficiencies.