Isolation, Characterization, and Pharmacological Potential of Hexapicenol From the Endemic Nepeta baytopii as a New Terpenoid: A Combination Analysis of in Vitro, in Silico, ADMET, and PASS

Abstract

The present study isolated a novel terpenoid, hexapicenol, from the endemic Nepeta baytopii Hedge & Lamond, a widespread and bioactive Nepeta genus in nature. The compound's pharmacological potential was supported by both in vivo and in silico studies as well as ADMET and PASS analyses. Hexapicenol exhibited a significantly effective antioxidant activity performance and was compared with the standards. Notably, the hexapicenol compound displayed superior DNA protection capacity, with 70.33 % protection in the Form I structure, surpassing the positive control. Enzymatic inhibition assays revealed potent effects of hexapicenol on urease and carbonic anhydrase (CA), with IC50 values of 16.94+0.04 and 3.79+0.42 mu M, respectively, exceeding the efficacy of reference standards. Hexapicenol (IC50, 30.21+0.02 mu g/mL) has similar anti-inflammatory activity to the standard. Molecular docking studies identified a strong binding affinity to alpha-glucosidase. The molecular dynamics simulations showed that the urease-hexapicenol complex formed a more stable structure than CA and alpha-glucosidase complexes. Moreover, MM/PBSA analysis confirmed higher binding energy for the CA-hexapicenol complex than other enzyme complexes. Density Functional Theory (DFT) calculations revealed a HOMO-LUMO energy gap (Egap) of 6.476 eV, with a high global hardness value, indicating pronounced electrophilic behavior and a tendency for slow reactivity, in line with the HSAB principle. In silico ADMET predictions suggested limited blood-brain barrier (BBB) permeability and moderate absorption. Hexapicenol demonstrated low toxicity. PASS analysis predicted several potential pharmacological activities, including antineoplastic, anti-inflammatory, antieczematic, lipid peroxidase inhibitory, and oxidoreductase inhibitory effects. These findings highlight hexapicenol as a promising bioactive terpenoid with multifaceted therapeutic potential.