Efficacy of Tinospora cordifolia bioactives as agonists of Smoothened (Smo) receptor to promote oligodendroglial lineage induction for remyelination-based therapy.

Chronic demyelinating disorders, such as multiple sclerosis (MS), are characterized by poor remyelination. This is due to an inherent characteristic of regenerative processes wherein remyelination efficiency drops with aging. Spontaneous remyelination is restricted in MS because of the adult oligodendrocyte progenitor cells' (OPCs) inability to transform into myelinating oligodendrocytes (OLs). The failure to regenerate myelin following injury undermines the integrity of axons and makes them susceptible to degradation. To address this issue stem cell therapy has contributed to a multitude of protocols for induction of OPCs from stem cells. However, till date these protocols have many drawbacks, including excessive dependence on artificial agonists. We specifically targeted the Smoothened (Smo) receptor of the sonic hedgehog (SHH) signaling pathway, which is instrumental in driving oligodendrocyte differentiation and myelin regeneration. Through a rigorous in silico framework, we evaluated a virtual library of 175 bioactive compounds derived from Tinospora cordifolia. Our methodology integrated biological activity predictions, ADMET profiling, molecular docking, and binding affinity estimations (MM-GBSA) against the Smo receptor followed by Molecular dynamics (MD) simulations. The analysis successfully identified three top-performing ligands (5281712, 137706608 and 441833). The Tinospora cordifolia bioactive compounds 137706608 and 5281712 emerged as the superior candidates after MD simulation. These bioactives exclusively satisfied all essential pharmacokinetic parameters, exhibiting central nervous system activity, excellent blood-brain barrier permeability, zero Lipinski rule violations, and no P-glycoprotein efflux liability. Ultimately, this study establishes T. cordifolia bioactives 137706608 and 5281712 as highly promising, structurally stable potential Smo binder. This compound represents a breakthrough lead molecule for optimizing in vitro oligodendroglial lineage specification, paving the way for innovative and safer remyelination-based neuroregenerative therapies. But, in vitro assays for Smo activation, Gli reporter activity, OPC differentiation markers, and myelin-related gene expression studies are required for a confirmatory test for their clinical application.