Identification of small molecule sirtuin-1 inhibitors for treating acute myeloid leukemia based on molecular docking, quantitative structure-activity relationships and molecular dynamics / 药学学报

ABSTRACT

The purpose of this study was to discover novel inhibitors of sirtuin-1 (SIRT1) that could be used in the treatment of acute myeloid leukemia (AML). Eight potential SIRT1 inhibitors were identified from 231 511 natural drug-like molecules by virtual screening-based molecular docking and molecular mechanics-generalized Born surface area (MM-GBSA) calculation of binding free energies. Using existing SIRT1 inhibitor molecules as training and test sets, a series of quantitative structure-activity relationship models were established, and the best quantitative structure-activity relationship (QSAR) model was used to predict the IC50 of these 8 potential inhibitor molecules for SIRT1. Subsequently, molecular dynamics simulations were performed to verify the binding mode and stability of these complexes of potential inhibitors and SIRT1 protein. Finally, the activity of these potential SIRT1 inhibitors was verified by cell proliferation assays of OCI-AML2, OCI-AML3 and MV4-11 cells and SIRT1 enzyme activity assays, and it was found that 5 compounds could inhibit AML cell proliferation. Among them, the most active compound, ZINC000001774455, had an IC50 of 2.29 ± 0.09 μmol·L-1 with OCI-AML2 cells, and at a concentration of 1 μmol·L-1, the inhibitory ratio of this compound on SIRT1 protein activity was 65.33%. ZINC000001774455 can be used as a lead compound for the development of new AML treatments.