The SARS-CoV-2 viruses use angiotensin-converting enzyme 2 (ACE2) to enter the human body. Infections are initiated by the binding of transmembrane spike (S) glycoprotein to the peptidase domain of human ACE2 (hACE2). A recent structural analysis reported the presence of two hotspots in hACE2 where the receptor-binding domain of the SARS-CoV-2 virus attached, namely hotspot-31 and hotspot-353. Our work studied the molecular interaction of diterpenoid lactones of Andrographis paniculata and the hydroxybenzylidene derivates of andrographolide with these hotspots in the peptidase domain of hACE2. The X-ray crystal structure of hACE2 was downloaded from RCSB Protein Data Bank (https://www. rcsb. org/). The ligands were built using MarvinSketch of ChemAxon and were subjected to energy minimization using the MMFF94 forcefield partial charges in the LigandScout software. The energy-minimized ligands were docked to both hotspots of hACE2. The results indicated that of all test ligands, only andrographolide could occupy hotspot-353 by building hydrogen bonds with Lys353, Glu37, and Asp38, and possesses the best docking score (-6.20 kcal/mol). Thus, andrographolide might be able to prevent the fusion of SARS-CoV-2 to hACE2 by occupying the site where the viruses attach to.