Inhibitory selectivity to the AKR1B10 and aldose reductase (AR): insight from molecular dynamics simulations and free energy calculations.

AKR1B10 is over-expressed in many cancer types and is related to chemotherapy resistance, which makes AKR1B10 a potential anti-cancer target. The high similarity of the protein structure between AKR1B10 and AR makes it difficult to develop highly selective inhibitors against AKR1B10. Understanding the interaction between AKR1B10 and inhibitors is very important for designing selective inhibitors of AKR1B10. In this study, Fidarestat, Zopolrestat, MK184 and MK204 bound to AKR1B10 and AR were used to investigate the selectivity mechanism. The results of MM/PBSA calculations show that van der Waals and electrostatic interaction provide the main contributions of the binding free energy. The hydrogen bonding between residues Y49 and H111 and inhibitors plays a pivotal role in contributing to the high inhibitory activity of AKR1B10 inhibitors. The π-π stacking interaction between residue W112 and inhibitor also plays a key role in the stability of inhibitors and AKR1B10, but W112 should keep its natural conformation to stabilize the inhibitor-AKR1B10 complex. Highly selective AKR1B10 inhibitors should have a bulky moiety like a phenyl group, which can change its binding with ABP in binding with AR and cannot change its binding with AKR1B10. The free energy decomposition shows that residues W21, V48, Y49, K78, W80, H111, R298 and V302 are beneficial to the stability of the inhibitor-AKR1B10. Our work will provide an important