Investigating the binding mechanism of sphingosine kinase 1/2 inhibitors: Insights into subtype selectivity by homology modeling, molecular dynamics simulation and free energy calculation studies

• Published in: Journal of molecular structure 2020-05, Vol.1208, p.127900, Article 127900
• Main Authors: Zhang, Jinmiao, Zhang, Maoyu, Yu, Jinying, Shang, Yanguo, Jiang, Kaixuan, Jia, Yihe, Wang, Jinxin, Yang, Kan
• Format: Article
• Language: English
• Subjects: Inhibitors; Molecular dynamics simulation; Selectivity; Sphingosine kinase
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2020.127900

Sphingosine 1-phosphate (S1P) is a lipid signaling molecule that is implicated in a variety of pathologies, including cancer, inflammation and pulmonary arterial hypertension. Sphingosine kinases (SPHK1 and SPHK2) are the key targets in the synthesis of S1P. However, selective and potent inhibitors of SPHK are lacking, especially for SPHK2. In this work, we predicted the detailed interactions between the inhibitors and SPHK using various molecular modeling methods. As a result, some residues (Asp 81, Ile174, Asp178, Phe288 of SPHK1 and Leu297, Ser298, Asp308 of SPHK2) were found as key binding sites of their inhibitors. The reason why PF543 is highly SPHK1 selective might be that its sulfonyl group conflicts with residue His556 of SPHK2. In SPHK1, the corresponding residue is His397. Compounds with a substituent occupying the pocket made up by His397 may show high selectivity towards SPHK1. Moreover, in case of SPHK2, introducing suitable substituents that insert into the region of Cys533 or designing a flexible polar head that interacts with Leu297 and Ser298 might improve the selectivity towards SPHK2. •Molecular modeling were used to predict the interactions between SPHK2 and its inhibitor K145.•Molecular dynamics simulations disclosed key binding sites in SPHK1 and SPHK2.•Some key principles were proposed to direct the design of SPHK1-selective or SPHK2-selective inhibitors.