Identification of potential SPHK1 inhibitors based on structural optimization by molecular simulation

Sphingosine Kinase 1 (SPHK1), observed to be overexpressed in an array of human malignancies, plays a pivotal role in modulating essential cellular activities throughout the process of tumor formation. Consequently, SPHK1 represents a promising therapeutic target, offering novel approaches to tumor treatment. Here, the structure-activity relationship was researched by using CoMFA and CoMSIA models. Both CoMFA (q²=0.621; <i>n</i> = 10; r²=0.992) and CoMSIA (q²=0.585; <i>n</i> = 7; r²=0.967) demonstrated satisfactory predictive capabilities. The structure-activity relationship of the compounds was analyzed by the counter maps of various fields. Further on, the compounds were interfaced with SPHK1 using the Surfex-Dock method to elucidate their interactive characteristics. Findings reveal that the binding is predominantly reliant on van der Waals, carbon-hydrogen bonds and hydrophobic interactions. Furthermore, the potential activities and ADME/T properties of six novel compounds were predicted utilizing 3D-QSAR models and online tools. The newly designed compounds were validated to have better activities and suitable ADME/T properties. In addition, molecular dynamics (MD) simulation further revealed that key residues, such as Ala339, Ala170, Ala115, Asp81, Gly342, Phe288 Ser164, Phe188, Ile170, etc. This study offers a roadmap to the discovery and design of innovative SPHK1 inhibitors.