In Silico Insights of Tunable Small Molecules With Regulatory Activity of Acid Sphingomyelinase-Protein Kinase Cδ Interaction

Abstract Acid sphingomyelinase demonstrates a housekeeping role and plays a key role in maintaining membrane turnover through sphingolipid metabolism. While deficiency of ASM housekeeping function leading to a lysosomal storage disorder, activation and translocation of ASM leads to AD pathology. Phosphorylation of ASM by PKCδ is critical for translocation of ASM to the plasma membrane. However, several strategies have been developed for the treatment of patients with AD, limitations of treatments and occurrence of AD by alternative signaling pathways become hurdle to the mortality of patients. In the present study, we report the interface of ASM- PKCδ interactions by performing molecular modeling, docking and dynamics simulation analysis. By considering the interacting site of ASM with PKCδ as an allosteric site, we screened a large number of small molecules by virtual screening and identified four lead molecules that show high binding affinity and interacting mode with residues of ASM that are critical to making interaction with PKCδ. The proven role of ASM in apoptosis, neurodegenerative diseases, and the existing functionality of leads in these diseases, together with strengthens the lead compounds, ZINC85551993, ZINC71928291, ZINC71773625 and ZINC85432419 as allosteric inhibitors for ASM. We believe that the lead molecules could be potential allosteric modulators for the translocation of ASM.