(LB02-01-25) Shatavarin IV Targets Receptor Tyrosine Kinases (RTK) in Promoting Neuronal Health: An In Silico Investigation

Objectives: This in silico study investigated the neuroprotective abilities of Shatavarin IV, a steroidal saponin of Asparagus racemosus.

Methods: Gene Ontology (GO) was employed to unravel functions of proteins which potentially interact with Shatavarin IV. Kyoto Encyclopedia for Genes and Genomes (KEGG) gene enrichment analysis identified the biological processes involved therein. The results were validated using STITCH database and molecular docking in Biovia Discovery Studio Visualizer.

Results: GO for biological process analysis indicated Shatavarin IV’s involvement in forebrain and cerebellar development. GO for molecular function revealed Shatavarin IV’s putative interaction with ephrin receptor (Eph), a RTK involved in axonal elongation and Long Term Potentiation (LTP). GO and KEGG studies confirmed Shatavarin IV’s involvement in the RTK family ErBb pathway for neuronal differentiation, synapse formation, and glial cell function. Molecular docking validated Shatavarin IV’s interactome as predicted by database screening. Shatavarin IV interacted strongly with Eph receptor with a free energy of -10.3 kcal/mole employing hydrogen bonds, ionic and Pi-alkyl interactions. Stronger binding was detected with ErBb3 receptor (△G = -11.3 kcal/mole) employing Carbon-H, alkyl , H- and pi-alkyl bonds. The Brain-Derived Neurotrophic factor (BDNF)-Tropomyosin related Kinase B (TrkB) axis is a major signaling pathway implicated in differentiation of neurons. Shatavarin IV interacted with TrkB as strongly as BDNF (△G = -9.9 kcal/mole) using Pi-alkyl, alkyl, hydrogen and Pi-sigma bonds. Shatavarin IV’s role in augmenting the function of RTKs was corroborated by STITCH analysis which confirmed its strong interaction with imatinib and dasatinib, inhibitors of RTKs widely employed in therapeutics.

Conclusions: The membrane associated RTKs are molecular targets of Shatavari and may underlie the mechanistic underpinnings of Shatavarin IV’s role in promoting neuronal health. Further research should explore RTKs as novel targets for designing Shatavarin IV-based therapeutics.

Funding Sources: This study was funded by Cepham Inc., Somerset, NJ, USA