Molecular Docking and Pharmacological Investigations of Folenolide for Its Analgesic, Anti-Inflammatory and Antipyretic Applications

Faryal Liaqat Ali¹Fazli Khuda¹Atif Ali Khan Khalil²Asif Jan¹Abdur Rasheed¹Muhammad Asif Khan³Syed Shaukat Ali¹Asmat Ullah^4*

• ¹University of Peshawar, Peshawar, Pakistan
• ²Yeungnam University, Gyeongsan-si, Republic of Korea
• ³Sarhad University of Science & Information Technology, Peshawar, Pakistan
• ⁴Spinghar University Faculty of Medicine, Jalalabad, Afghanistan

Background: Folenolide, a novel compound, was investigated for its pharmacological potential, focusing on its analgesic, anti-inflammatory, and antipyretic effects, along with its safety profile and potential molecular targets, using in-vivo models and molecular docking studies. Methods: In-vivo models mouse models were used to assess acute toxicity and analgesic, anti-inflammatory, and antipyretic activity. Molecular docking simulations were conducted against key targets, including COX-2, lipoxygenase, opioid, histamine, and tankyrase receptors, to explore their potential mechanisms of action. Results: Folenolide showed no signs of acute toxicity. The analgesic model exhibited significant peripheral analgesia in the acetic acid-induced writhing test (31.07% and 50.13% inhibition at 3 and 6 mg/kg, respectively; p< 0.01) and potent central analgesia in the hot plate test (maximum effect at 6 mg/kg; p< 0.0001). Formalin test results confirmed both neurogenic and inflammatory phase inhibition (69.17–78.26%). Anti-inflammatory efficacy was marked in carrageenan-induced paw edema (84.3–94.98% reduction), histamine-induced edema (87.29–88.6%), and xylene-induced ear edema (6.19–8.19% weight gain suppression) (p< 0.05). Folenolide also displayed antipyretic effects, significantly reducing the rectal temperature in yeast-induced fever models. Molecular docking revealed favorable binding affinities (ΔG ranging from -4.4 to -5.9 kJ/mol) with key targets. Conclusions: Folenolide exhibits strong analgesic, anti-inflammatory, and antipyretic activities with a favorable safety profile. Its pharmacodynamic effects are supported by its molecular interactions with cyclooxygenase (COX), opioids, and histamine receptor targets. These findings highlight its potential as a promising therapeutic agent for pain, inflammation, and fever management.