3‐Hydroxy‐3‐Methylglutaryl Coenzyme‐A Inhibitory Activity of <i>Padina pavonia</i> Terpenoids: An Integrated In Vitro and In Silico Exploration

The inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMGCR) activity carries considerable therapeutic significance, prompting the investigation of novel inhibitors to tackle associated health conditions and improve patient care. Seeking non statin scaffolds, we provide the first integrated evaluation of six terpenoids isolated from the brown alga Padina pavonia, expanding the species' chemical repertoire and establishing their activity against HMGCR. We have previously shown the anti-hyperlipidemia activity of P. pavonia terpenoid-rich fraction. Herein, we evaluated the inhibitory potential of six P. pavonia terpenoids against HMGCR, employing both in vitro and in silico methodologies. All terpenes inhibited HMGCR, with compound 1 being the most potent (IC₅₀ = 17.93 ± 1.78 µM), followed by compound 5 (IC₅₀ = 22.47 ± 1.59 µM) and compound 2 (IC₅₀ = 24.51 ± 2.13 µM). Molecular docking revealed that all compounds have affinity toward HMGCR, and compounds 1 and 2 are effectively bound to the same active site as the reference drug atorvastatin. Molecular dynamics (MD) simulations depicted notable energy stabilization and consistent trajectory profiles of the terpenes-HMGCR complexes. The results of Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis depicted the lowest binding free energies for compounds 1 and 5 (-7.00 ± 1.00 and -7.06 ± 2.24 kJ/mol, respectively). These findings along with the limited number of detected hydrogen bonds and the results of interaction energy calculations suggest that the formed complexes are mainly influenced by attractive forces associated with van der Waals interactions rather than electrostatic interactions. In vitro experiments revealed the inhibitory activity of all isolated terpenes, with compound 1 exhibiting the most potent activity. Therefore, terpenoids of P. pavonia represent promising candidates for the development of HMGCR inhibitors.