Comparative in-Silico Profiling of Adme, Drug Likeness, and Target Prediction of Spisulosine and Selected Analogues

Spisulosine, also known as ES-285, is an anticancer compound isolated from a marine organism, Spisula polynyma, and has shown significant preclinical potential, but its clinical trial was discontinued in 2008 due to dose-limiting neurotoxicity. This study implements an in-silico approach to effectively evaluate the pharmacokinetic, ADME (Absorption, Distribution, Metabolism, Excretion) profiles, integrated with molecular target prediction, for ES-285 and three of its analogues: Xestoaminol C, 3-epi-Xestoaminol C, and 1-Deoxysphingosine, using SwissADME and SwissTargetPrediction web tools, for pharmacokinetic and target predictions. All compounds demonstrated high predicted gastrointestinal absorption and blood-brain barrier (BBB) permeation, consistent with the neurotoxic effect. A significant difference in metabolic profiles was observed, with Spisulosine and 1-Deoxysphingosine predicted to inhibit multiple cytochrome P450 (CYP) isoforms, suggesting a high risk for drug-drug interactions, while Xestoaminol C and 3-epi-Xestoaminol C showed a limited inhibition profile, affecting only CYP2D6, although none of the compounds inhibited CYP3A4. The predicted primary molecular target of Spisulosine and its analogues was sphingosine kinase 1 (SPHK1), validating their anticancer property. These findings highlight the potential of Xestoaminol C and 3-epi-Xestoaminol C as promising leads for further chemical optimization, particularly for reducing BBB penetration and improving the overall therapeutic window of this class of compounds.