Computational and Molecular Docking Analysis of ?-Sitosterol from Turmeric as a Potential Therapeutic Agent for Ulcerative Colitis

Abstract

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by recurrent mucosal ulceration, diarrhea, abdominal pain, and weight loss. Conventional therapies, including aminosalicylates, corticosteroids, and immunosuppressants, provide symptomatic relief but are often associated with adverse effects and incomplete remission. In recent years, natural phytochemicals have gained attention as alternative or complementary therapeutic options. ?-Sitosterol, a bioactive phytosterol abundantly present in turmeric, has demonstrated anti-inflammatory and immunomodulatory properties. Emerging evidence suggests that ?-sitosterol exerts its effects by modulating the NF-?B signaling pathway and activating peroxisome proliferator-activated receptor-? (PPAR-?), thereby reducing pro-inflammatory cytokine expression and restoring intestinal homeostasis. In this study, molecular docking was employed to predict the binding affinity and interaction patterns of ?-sitosterol with key UC-related targets. The docking simulations revealed favorable binding energies, supported by hydrogen bonding, hydrophobic interactions, and van der Waals forces, indicating strong protein–ligand interactions. These findings suggest that ?-sitosterol could serve as a promising lead compound for the development of safer and more effective therapeutics for UC. Further in vitro and in vivo studies are required to validate its therapeutic potential.

Keywords

Introduction

Figure 1: 3D Structure of beta sitosterol

Figure 2: 3D Structure interaction of beta sitosterol with 3GBK protein

β-Sitosterol: Highly lipophilic, extremely poor solubility, predicted low GI absorption. No major CYP or P-gp risks but limited oral bioavailability; requires formulation strategies.

Mesalamine: Very soluble and polar, limited passive permeability. Effective mainly for local intestinal action; colon-targeted formulations preferred.

Budesonide: Moderate lipophilicity, soluble, high GI absorption but P-gp substrate. Good oral/colon-targeted drug profile with controlled release; first-pass metabolism reduces systemic effects.

RESULT AND DISCUSSION:

Docking simulations were carried out to compare the binding affinity of β-sitosterol with the reference drugs budesonide and mesalamine against the 3GBK protein. The analysis revealed a distinct hierarchy in binding potential. β-Sitosterol demonstrated the strongest affinity (−9.1 kcal/mol), primarily due to a favorable hydrophobic fit within the active pocket. It engaged in extensive van der Waals and hydrophobic interactions with residues Leu198, Val121, Leu141, Val143, Phe131, and Trp209, while its hydroxyl group established a weak hydrogen bond with Thr199/Thr200. Although the sterol core was located near the His94–His96–His119 Zn²? triad, no direct metal coordination occurred, indicating a non-classical inhibition pattern characterized by steric hindrance and hydrophobic stabilization. Budesonide showed a binding energy of −7.3 kcal/mol and maintained a balanced network of hydrophobic and polar interactions. When considered alongside its favorable ADME characteristics, including solubility and oral bioavailability, budesonide emerged as the most practical and drug-like candidate. In contrast, mesalamine exhibited the weakest binding affinity (−5.0 kcal/mol), with only limited polar interactions in the active site, consistent with its known therapeutic role as a locally acting anti-inflammatory agent within the gut rather than a systemic binder.

SwissADME evaluation indicated that β-sitosterol, while exhibiting strong binding affinity, is limited by poor water solubility, high lipophilicity, and low oral absorption, which could restrict its therapeutic effectiveness in vivo. In contrast, budesonide demonstrated favorable pharmacokinetic characteristics, including good gastrointestinal absorption and acceptable drug-likeness, consistent with its established clinical success in managing ulcerative colitis. Mesalamine, although not meeting several drug-likeness criteria, retains clinical relevance owing to its localized action in the colon with minimal systemic uptake. Toxicity assessment using ProTox-II classified β-sitosterol as relatively safe, with no major organ-specific toxicity signals, though its limited bioavailability remains a key drawback.

The results reveal a clear gap between theoretical affinity and practical drug-likeness. Although β-sitosterol binds most strongly receptor, its poor pharmacokinetics limit systemic use unless improved by structural modifications or advanced formulations. Budesonide, with moderate docking strength but superior ADME properties, stands out as the most viable candidate, aligning with its established role in UC treatment. The weak binding of mesalamine supports its function as a locally acting anti-inflammatory. Overall, β-sitosterol may serve as a promising natural scaffold for UC drug development pending experimental validation, while budesonide remains the benchmark therapeutic due to its balanced efficacy and safety.

CONCLUSION:

This study demonstrates that β-sitosterol exhibits the strongest theoretical binding affinity toward the 3GBK receptor, primarily driven by hydrophobic interactions, yet its poor solubility, lipophilicity, and limited absorption significantly restrict its systemic therapeutic potential. Budesonide, although showing moderate docking affinity, combines favorable ADME and safety properties, reaffirming its clinical utility as an effective UC treatment. Mesalamine, with weak binding, remains relevant due to its localized colonic action rather than systemic receptor inhibition. Collectively, these findings suggest that β-sitosterol holds promise as a natural scaffold for future UC drug development, provided pharmacokinetic limitations are addressed through structural modification or novel delivery systems, while budesonide continues to represent the optimal benchmark therapy.

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