Discovery and design of dual inhibitors targeting Sphk1 and Sirt1

Abstract

Context: Leukaemia has become a serious threat to human health. Although tyrosine kinase inhibitors (TKIs) have been developed as targets for the remedy of leukaemia, drug resistance occurs. Research demonstrated that the simultaneous targeting of sphingosine kinase 1 (Sphk1) and Sirtuin 1 (Sirt1) can downregulate myeloid cell leukaemia-1 (MCL-1), overcome the resistance of tyrosine kinase inhibitors, and play a synergistic inhibitory impact on leukaemia treatment.

Methods: In this study, virtual screening of 7.06 million small molecules was done by sphingosine kinase 1 and Sirtuin 1 pharmacophore models using Schrödinger version 2019; after that, ADME and Toxicity molecule properties were predicted using Discovery Studio. Molecular docking using Schrödinger selected five molecules, which have the best binding affinity with sphingosine kinase 1 and Sirtuin 1. The five molecules and reference inhibitors were constructed with a total of 12 systems with GROMACS that carried out 100 ns molecular dynamics simulation and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculation. Due to compound 3 has the lowest binding energy, its structure was modified. A series of compounds docked with sphingosine kinase 1 and Sirtuin 1, respectively. Among them, QST-LC03, QST-LD05, QST-LE03, and QST-LE04 have the better binding affinity than reference inhibitors. Moreover, the SwissADME and PASS platforms predict that 1, 3, QST-LC03, and QST-LE04 have further study value.

Keywords: Dual target inhibitors; Dynamics simulation; Leukaemia; Virtual screening.