Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

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

Mahmoud Kandeel^1,2 , Abdulla Al-Taher¹, Mohammed Al-Nazawi¹, Kantaro Oh-hashi^3,4

¹Department of Physiology, Biochemistry, and Pharmacology, College of Veterinary Medicine, King Faisal University, 31982 Al-Ahsa, Saudi Arabia; ²Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt; ³Department of Chemistry and Biomolecular Science, Faculty of Engineering; ⁴United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.

For correspondence:- Mahmoud Kandeel Email: mkandeel@kfu.edu.sa Tel:+966568918734

Accepted: 25 July 2019 Published: 28 August 2019

Citation: Kandeel M, Al-Taher A, Al-Nazawi M, Oh-hashi K. Substructural dynamics of the phase-I drug metabolizing enzyme, carbonyl reductase 1, in response to various substrate and inhibitor configurations. Trop J Pharm Res 2019; 18(8):1635-1641 doi: 10.4314/tjpr.v18i8.10

© 2019 The authors.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..

Abstract

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 α-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 α-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.

Keywords: Carbonyl reductase, Phase-1 metabolism, Molecular dynamics, Docking