Disrupting Cancer Metabolism: Molecular Docking Insights into Andrographolides as a Competitive Inhibitors of Selected Lipogenic Enzymes (Fatty Acid Synthase, ATP Citrate Lyase, and Acetyl-CoA Carboxylase)

Abstract

Cancer remains a significant global health challenge, with metabolic dysregulation emerging as a critical focus in cancer research. Aberrant de novo lipogenesis has been identified as a hallmark of various malignancies. Key enzymes in this pathway including fatty acid synthase (FASN), ATP citrate lyase (ACLY), and acetyl-CoA carboxylase alpha (ACCα). Overexpression of these enzymes facilitate fatty acid production, supports tumor growth by contributing to membrane biosynthesis, energy storage, and signaling. Andrographolide, a bioactive compound derived from Andrographis paniculata, has demonstrated anti-cancer properties by inhibiting de novo lipogenesis. This study aimed to elucidate the molecular docking interactions and inhibitory effects of andrographolide towards lipogenic enzymes. Docking analyses revealed that andrographolide targets FASN’s thioesterase (TE) domain (residues S101 and H237) and enoyl reductase (ER) domain (residues 1671–1688) with a binding affinity of -2.14 and -1.92 kcal/mol respectively. Similarly, andrographolide interacted with ACCα’s carboxyltransferase (CT) domain (residues A1722, I1724, I1827, I2126, and K2127), showing a binding affinity of -1.32 kcal/mol. However, its interaction with ACLY at residue F347 yielded a binding affinity of -1.62 kcal/mol, with evidence suggesting that F347 may not be involved in stable citrate interactions due to poorly resolved electron density. The inhibition of enzyme disrupts the production of long-chain fatty acids essential for cancer cell growth, restricts the energy and structural demands of rapidly dividing cancer cells, and hinders their survival, progression, and metastatic potential, offering a promising therapeutic approach for multiple cancer types.