Computational determination of binding structures and free energies of glucose 6-phosphate dehydrogenase with novel steroid inhibitors

• The detailed binding of G6PD with the steroid DHEA derivatives has been studied by performing molecular docking, MD simulations, and binding free energy calculations.
• The calculated binding free energies of the enzyme with the inhibitors using MM/PBSA method are qualitatively consistent with the experimental activity data.
• The important, favorable interactions between the enzyme and the inhibitors have been revealed and main factors affecting the binding have been discussed.

Glucose 6-phosphate dehydrogenase (G6PD), the first and the rate-limiting enzyme in the pentose phosphate pathway (PPP), catalyzes the oxidation of G6P to 6-phosphogluconolactone and the reduction of NADP+ to NADPH. Its key role in cancer promotes the development of a potent and selective inhibitor that might increase cancer cell death when combined with radiotherapy. In the present study, we investigated the detailed binding modes and binding free energies for G6PD interacting with a promising series of recently developed inhibitors, i.e., the steroid derivatives, by performing molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. The docking indicates that the inhibitors occupy the binding sites of both G6P and NADP+. The calculated binding free energies on the basis of the MD-simulated enzyme–inhibitor complexes are in good agreement with the experimental activity data for all of the examined inhibitors. The valuable insights into the detailed enzyme–inhibitor binding including the important intermolecular interactions, e.g., the hydrogen bond interaction and the hydrophobic interaction, have been provided. The computational results provide new insights into future rational design of more potent inhibitors of G6PD as a treatment for cancer.

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