MOLECULAR DOCKING AND ADMET ANALYSIS OF CUCURBITACIN B AGAINST HMG-CoA REDUCTASE: A COMPARATIVE IN SILICO STUDY WITH PRAVASTATIN AND IMPLICATIONS FOR LIPID-LOWERING AND PROGERIA MANAGEMENT

Hyperlipidemia and Hutchinson-Gilford Progeria Syndrome (HGPS) are mechanistically distinct disorders that converge at a common metabolic node, the mevalonate pathway, specifically at HMG-CoA reductase. While statins - such as pravastatin, remain the standard inhibitors of this enzyme. A natural triterpenoid, such as cucurbitacin B (a bioactive compound from Cucurbita pepo) have demonstrated diverse pharmacological properties but remain unexplored as HMG-CoA reductase inhibitors. This study aimed to compare the binding affinity, pharmacokinetic profile and toxicity of cucurbitacin B against pravastatin using molecular docking and ADMET analysis. The 3D structures of the both compounds were retrieved from PubChem database and human HMG-CoA reductase was taken as the target for molecular docking. Predictive models including SwissDock and MzDOCK were employed to carry out molecular docking, whereas, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were predicted using SwissADME and ProTox 3.0 servers. Cucurbitacin B demonstrated a better binding affinity than pravastatin with a score of −7.398 kcal/mol and −5.858 kcal/mol using SwissDock and a score of −8.2 and −7.7 kcal/mol using MzDOCK respectively. It formed hydrophobic, hydrogen bond, and salt bridge interactions with amino acid residues of the enzyme active site. The ADMET properties of cucurbitacin B were found to be better than those of pravastatin with an exception that it exhibited a higher molecular weight (547.58 versus 406.54 g/mol), higher lipophilicity (4.79 versus 1.27), poor gastrointestinal absorption, but the oral bioavailability of Cucurbitacin B can be improved using advance drug delivery technology like micelles or nanoparticles-based formulation. It was also predicted to have a low oral LD50 (14 mg/kg, class 2) compared to pravastatin (8939 mg/kg, class 6), this highlighting a key safety concern. These findings suggest that cucurbitacin B may represent a potential lead scaffold for HMG-CoA reductase targeted investigation in Hyper-lipidemia and HGPS; however, its predicted toxicity highlights the need for further safety evaluation and structural optimization.

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