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Exploring the interactional details between aldose reductase (AKR1B1) and 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid through molecular dynamics simulations
Authors:Jiu-Yu Zhan  Ke Ma  Guang-Hui Yang  Hong-Xing Zhang
Affiliation:1. International Joint Research Laboratory of Nano-Micro Architecture Chemistry, Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University , Changchun 130023, People’s Republic of China;2. Department of Pediatric Outpatient, The First Hospital of Jilin University , Changchun 130021, People’s Republic of China;3. Jilin Provincial Institute of Education , Changchun 130022, People’s Republic of China
Abstract:
Aldose reductase (AKR1B1) has been considered as a significant target for designing drugs to counteract the development of diabetic complications. In the present study, molecular dynamics (MD) simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to make sure which tautomer is the preferred one among three tautomeric forms (Mtia1, Mtia2, and Mtia3) of 3-Mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (Mtia) for binding to AKR1B1. The overall structural features and the results of calculated binding free energies indicate that Mtia1 and Mtia2 have more superiority than Mtia3 in terms of binding to AKR1B1. Furtherly, the local active site conformational characteristics and non-covalent interaction analysis were identified. The results indicate that the combination of Mtia2 and AKR1B1 is more stable than that of Mtia1. Furthermore, two extra hydrogen bonds between AKR1B1 and Mtia2 are found with respect to Mtia1. In addition, Mtia2 makes slightly stronger electrostatic interaction with the positively charged nicotinamide group of NADP+ than Mtia1. Based on the results above, Mtia2 is the preferred tautomeric form among the three tautomers. Our study can provide an insight into the details of the interaction between AKR1B1 and Mtia at the atomic level, and will be helpful for the further design of AKR1B1 inhibitors.
Keywords:molecular dynamics  aldose reductase  MM-GB/SA calculation  inhibitor  tautomer
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