Identification of potential SPHK1 inhibitors based on structural optimization by molecular simulation
Year: 2025
Type: article
Abstract: 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; n = 10; r2=0.992) and CoMSIA (q2=0.585; n = 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.
Source: Figshare
Authors: Zhao, Xuemin, Zhang, Lu, Yu, Na, Shu, Mao
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W6939716024
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