Preliminary In Silico Evaluation of Potential Therapeutics for Non-Alcoholic Steatohepatitis (NASH) using Molecular Docking and Pharmacokinetics Analysis

Abstract

Non‑alcoholic steatohepatitis (NASH) is a progressive inflammatory liver disease arising from non‑alcoholic fatty liver disease (NAFLD) and is increasingly prevalent due to rising obesity, insulin resistance, and sedentary lifestyle. Its pathology is driven by a complex interplay of metabolic dysfunction, oxidative stress, lipotoxicity, and chronic inflammation involving immune cells such as Kupffer cells, macrophages, and T lymphocytes. Despite the high global disease burden, no FDA‑approved pharmacological therapy exists. This has accelerated the search for new therapeutic candidates. In this preliminary in silico investigation, we screened bioactive phytochemicals and approved/experimental synthetic molecules against tumor necrosis factor‑α (TNF‑α), a key cytokine implicated in NASH‑associated hepatic inflammation. Forty literature‑supported compounds were evaluated for drug‑likeness using Lipinski, Veber, and Egan filters, followed by molecular docking using AutoDock Vina. Selected top‑ranked ligands underwent ADME analysis via SwissADME and toxicity prediction via ProTox‑II. Unlike initial plant-name–based screening, this corrected version uses well‑defined molecular structures (e.g., 6‑gingerol, rosmarinic acid, boswellic acid) to ensure chemical rigor. Docking revealed that Selonsertib, Silymarin, Daidzein, and Apigenin exhibited strong binding affinity toward TNF‑α with biologically relevant interaction residues. ADME evaluation showed acceptable solubility, lipophilicity, non‑inhibition of critical CYP isoforms for selected candidates, and favorable bioavailability scores. Toxicity analysis further narrowed down five compounds with non‑fatal toxicity classes (Class 4–5). These findings highlight potential NASH therapeutics warranting further validation through molecular dynamics simulations and experimental studies.