Investigation of sphingosine kinase 1 inhibitory potential of cinchonine and colcemid targeting anticancer therapy

Abstract

Sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) signaling regulates numerous diseases such as cancer, diabetes, and inflammation-related ailments, rheumatoid arthritis, atherosclerosis, and multiple sclerosis. The importance of SphK1 in chemo-resistance has been extensively explored in breast, lung, colon, and hepatocellular carcinomas. SphK1 is considered an attractive drug target for the development of anticancer therapy. New drug molecules targeting the S1P signaling are required owing to its pleiotropic nature and association with multiple downstream targets. Here, we have investigated the binding affinity and SphK1 inhibitory potential of cinchonine and colcemid using a combined molecular docking and simulation studies followed by experimental analysis. These compounds bind to SphK1 with a significantly high affinity and subsequently inhibit kinase activity (IC₅₀ 7–9 μM). Further, MD simulation studies revealed that both cinchonine and colcemid bind to the residues at the active site pocket of SphK1 with several non-covalent interactions, which may be responsible for inhibiting its kinase activity. Besides, the binding of cinchonine and colcemid causes substantial conformational changes in the structure of SphK1. Taken together, cinchonine and colcemid may be implicated in designing potential drug molecules with improved affinity and specificity for SphK1 targeting anticancer therapy.

Communicated by Ramaswamy H. Sarma

Keywords:

• Sphingosine kinase-1
• sphingosine-1-phosphate
• cell signaling
• cancer therapy
• drug target
• colcemid
• kinase inhibitors
• drug discovery
• MD simulation

Acknowledgments

SR is thankful to the University Grants Commission for the award of Senior Research Fellowship. SK would like to thank the University of the Witwatersrand for the funding of the URC postdoctoral fellowship and also thankful to CHPC, South Africa for providing the super-computer facility. SK would also like to acknowledge University of Cape Town's H3D, AMR platform for providing the financial assistance. MFA and AH acknowledge the generous support from the Research Supporting Project (No. RSP-2020-122) by King Saud University, Riyadh, Kingdom of Saudi Arabia.

Disclosure statement

The authors of this study do not report any conflicts of interest.

Additional information

Funding

This work is funded by the Indian Council of Medical Research, Government of India (Grant No. ISRM/12(22)/2020).