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

Ha Thi Nguyen,Vishala Chandi,Haritha Polimati,Thien-Y Vu,Vinay Bharadwaj Tatipamula

doi:10.1038/s41598-020-72840-8

Ha Thi Nguyen, Vishala Chandi + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-72840-8

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Abstract

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 IC50 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.

Highlights

Cyclooxygenases (COX-1/2) and lipoxygenases (LOX) are well-recognized as pro-inflammatory enzymes as well as vital enzymes in the metabolic pathway of arachidonic acid1
All of these compounds have been earlier reported from P. longifolia, it was the first time they were isolated from the seeds of this species
Based on the previous reports on the anti-inflammatory properties of the extracts of P. longifolia, we investigated the anti-inflammatory activities of these compounds in vitro

Summary

Introduction

Cyclooxygenases (COX-1/2) and lipoxygenases (LOX) are well-recognized as pro-inflammatory enzymes as well as vital enzymes in the metabolic pathway of arachidonic acid1 These enzymes are essential for the physiological production of eicosanoids, including leukotrienes, prostaglandins, and thromboxane, that primarily cause inflammation. It is noteworthy that COX/5-LOX co-inhibition potentially reduces side effects on the cardiovascular and gastrointestinal tract while retaining the primary activity of COX-1/2 inhibitors With this aim, darbufelone and licofelone were first designed and clinically used as a dual COX/5-LOX inhibitory anti-inflammatory drugs. We first isolated and identified the metabolites present in methanolic extracts of seeds of P. longifolia Afterward, these metabolites were screened for their potential COX-1/2 and 5-LOX dual inhibitory activities by performing in vitro experiments. Their dual inhibitory activity and binding mode were investigated in silico using Schrodinger suite 2020-2

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