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Discovery and design of dual inhibitors targeting Sphk1 and Sirt1
Jin Liu1, Hui-Lin Zhao1, Lei He1
1School of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
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.
Insights
This study identifies novel compounds that simultaneously target sphingosine kinase 1 (Sphk1) and Sirtuin 1 (Sirt1) to overcome drug resistance in leukaemia treatment.
Area of Science:
- Computational chemistry and drug discovery
- Molecular modeling and simulation
Background:
- Leukaemia poses a significant health risk, with drug resistance limiting current treatments like tyrosine kinase inhibitors (TKIs).
- Targeting sphingosine kinase 1 (Sphk1) and Sirtuin 1 (Sirt1) simultaneously shows promise in overcoming TKI resistance by downregulating myeloid cell leukaemia-1 (MCL-1).
Purpose of the Study:
- To identify novel small molecules with synergistic inhibitory effects against leukaemia by targeting Sphk1 and Sirt1.
- To computationally screen and validate potential drug candidates for enhanced leukaemia therapy.
Main Methods:
- Virtual screening of over 7 million small molecules using Sphk1 and Sirt1 pharmacophore models.
- In silico prediction of ADME/Toxicity, molecular docking, and molecular dynamics simulations (100 ns) with MM/PBSA calculations.
- Structure-based drug design and re-docking of modified compounds, followed by evaluation using SwissADME and PASS platforms.
Main Results:
- Five lead molecules exhibited strong binding affinity with both Sphk1 and Sirtuin 1.
- Modified compound 3 showed the lowest binding energy, leading to further structural optimization.
- Novel compounds QST-LC03, QST-LD05, QST-LE03, and QST-LE04 demonstrated superior binding affinity compared to reference inhibitors.
Conclusions:
- Compounds QST-LC03 and QST-LE04, along with initial compounds 1 and 3, show significant potential for further investigation in leukaemia treatment.
- The simultaneous targeting strategy of Sphk1 and Sirt1 offers a promising approach to overcome drug resistance in leukaemia.
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