Dual COX and 5-LOX inhibition by clerodane diterpenes from seeds of Polyalthia longifolia (Sonn.) Thwaites

• Published in: Scientific reports 2020-09, Vol.10 (1), p.15965, Article 15965
• Main Authors: Nguyen, Ha Thi, Vu, Thien-Y., Chandi, Vishala, Polimati, Haritha, Tatipamula, Vinay Bharadwaj
• Format: Article
• Language: English
• Subjects: 631/114; 631/92; 639/638; Arachidonate 5-Lipoxygenase - chemistry; Arachidonate 5-Lipoxygenase - metabolism; Computer Simulation; Cyclooxygenase 1 - chemistry; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Diterpenes, Clerodane - chemistry; Diterpenes, Clerodane - pharmacology; Humanities and Social Sciences; Humans; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Models, Molecular; Molecular Docking Simulation; Molecular Structure; multidisciplinary; Plant Extracts - chemistry; Plant Extracts - pharmacology; Polyalthia - chemistry; Science; Science (multidisciplinary); Seeds - chemistry
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-72840-8

Natural metabolites with their specific bioactivities are being considered as a potential source of materials for pharmacological studies. In this study, we successfully isolated and identified five known clerodane diterpenes, namely 16-oxo-cleroda-3,13(14)E-dien-15-oic acid (1) , 16-hydroxy-cleroda-3,13-dien-15-oic acid (2) , 16-hydroxy-cleroda-4(18),13-dien-16,15-olide (3) , 3α,16α-dihydroxy-cleroda-4(18),13(14)Z-dien-15,16-olide (4) , and 16α-hydroxy-cleroda-3,13(14)Z-dien-15,16-olide (5) from the methanolic extract of seeds of Polyalthia longifolia . Initially, all the isolated metabolites were investigated for COX-1, COX-2, and 5-LOX inhibitory activities using the standard inhibitory kits. Of which, compounds 3 , 4 , and 5 exhibited to be potent COX-1, COX-2, and 5-LOX inhibitors with the IC 50 values similar or lower to those of the reference drugs. To understand the underlying mechanism, these compounds were subjected to molecular docking on COX-1, COX-2, and 5-LOX proteins. Interestingly, the in silico study results were in high accordance with in vitro studies where compounds 3 , 4 , and 5 hits assumed interactions and binding pattern comparable to that of reference drugs (indomethacin and diclofenac), as a co-crystallized ligand explaining their remarkable dual (COX/LOX) inhibitor actions. Taken together, our findings demonstrated that compounds 3, 4, and 5 functioned as dual inhibitors of COX/5-LOX and can contribute to the development of novel, more effective anti-inflammatory drugs with minimal side-effects.