Identification of potential SPHK1 inhibitors based on structural optimization by molecular simulation
Xuemin Zhao1, Lu Zhang1, Na Yu1
1School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China.
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.
Insights
This study explores novel inhibitors for Sphingosine Kinase 1 (SPHK1), a key target in cancer. Using computational models, researchers identified promising compounds with improved activity and drug-like properties for potential tumor treatment.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Oncology
Background:
- Sphingosine Kinase 1 (SPHK1) is overexpressed in many human cancers.
- SPHK1 plays a critical role in tumor formation and progression.
- Targeting SPHK1 offers a potential therapeutic strategy for cancer treatment.
Purpose of the Study:
- To investigate the structure-activity relationship (SAR) of potential SPHK1 inhibitors.
- To design and predict the properties of novel SPHK1 inhibitors.
- To provide a computational roadmap for developing new anti-cancer agents targeting SPHK1.
Main Methods:
- Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) models were employed to analyze SAR.
- Surfex-Dock was used to elucidate the binding interactions between compounds and SPHK1.
- 3D-QSAR models and online tools predicted the activity and ADME/T properties of novel compounds.
- Molecular dynamics (MD) simulations were performed to further analyze binding interactions.
Main Results:
- CoMFA and CoMSIA models demonstrated satisfactory predictive capabilities for SAR (q² values of 0.621 and 0.585, respectively).
- Binding analysis revealed predominant van der Waals, carbon-hydrogen bonds, and hydrophobic interactions.
- Six newly designed compounds exhibited enhanced activities and suitable ADME/T properties.
- MD simulations identified key residues involved in SPHK1 inhibition.
Conclusions:
- The study successfully established SAR for SPHK1 inhibitors using 3D-QSAR.
- Novel compounds with promising anti-cancer potential and favorable drug-like properties were identified.
- This research provides a foundation for the rational design of innovative SPHK1-targeted cancer therapeutics.
