Exploring the Anti-diabetic Potential of Sida cordata: An In Silico Study through Molecular Docking and Dynamics Simulation

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Abstract
Background: Diabetes mellitus is a progressive metabolic disorder characterise by chronic hyperglycemia and impaired carbohydrate metabolism. Despite the availability of synthetic antidiabetic agents, their long-term administration is often associated with adverse effects, which stresses the urgent need for safer alternatives of plant origin. Sida cordata is a traditionally valued medicinal plant reported to exhibit antidiabetic and organ-protective actions; however, its detailed molecular mechanism for antidiabetic activity is not yet well established. Aim: To explore in depth, through in silico molecular docking and molecular dynamics simulations, the potential mechanisms of S. cordata phytoconstituents as an antidiabetic agent against important protein targets associated with diabetes. Methods: Twenty-eight S. cordata phytoconstituents were screened against four diabetes-related proteins (PDB IDs: 7VSI, 7WMV, 4EMA and 1KAV) using Schrödinger Glide for molecular docking. The stability and dynamic behavior of the top-scoring protein-ligand complexes were further investigated by molecular dynamics simulations conducted with GROMACS.ADMET and drug-likeness were predicted using SwissADME to assess pharmacokinetics. Results: The molecular docking analysis of all screened phytoconstituents revealed favorable binding affinities as evidenced by the obtained docking scores ranging from -1.4 to -12.9 kcal/mol. Notably, α-D-glucopyranoside, O-α-D-glucopyranosyl-(1→3)-α-D-fructofuranosyl exhibited the highest and most consistent binding to all targets, reaching a maximum docking score of -12.9 kcal/mol against 7VSI. Thus, an interaction analysis was conducted, which revealed stable hydrogen bonding and hydrophobic interactions within the active site. Molecular dynamics simulations demonstrated structural stability for both 7VSI-lead compound and 7VSI-standard complexes, with the least root-mean-square deviation for the entire period of the simulation study. The ADMET analysis revealed that the selected lead compound exhibited acceptable pharmacokinetic properties, good oral bioavailability, and no predicted toxicity. These findings support its drug-likeness and suitability for further antidiabetic development. The current findings support the antidiabetic potential of S. cordata, in particular its α-D-glucopyranoside derivatives, through in silico results indicating high binding affinities and biologically stable protein-ligand interactions with target proteins associated with diabetes. Major Findings: Sida cordata phytoconstituents demonstrated strong and consistent binding to multiple diabetes-related protein targets. The α-D-glucopyranoside derivative emerged as a stable lead compound, validated through molecular docking and dynamics simulations.

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