Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition.

Md Mominur Rahman,S M Zahid Hosen,Lei Liu,Md Junaid,Kirsten Benkendorff,Mohammad Mostafa

doi:10.3390/molecules26216538

Abstract

Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.

Highlights

Inflammation is an essential part of the immune response system [1] that is initiated by stimuli from pathogens, dust, and oxidative stress, following infection or injury to the tissue [2,3,4]
Known as prostaglandin-endoperoxide H synthase (PGHS), COX plays a vital role in the conversion of arachidonic acid (AA) into prostanoids [17]
Molecular docking is a standard approach for structure-based drug design to evaluate the atomic level interaction between small molecules and a protein; it helps to identify target specificity along with binding affinity [40,41,42]

Summary

Introduction

Inflammation is an essential part of the immune response system [1] that is initiated by stimuli from pathogens, dust, and oxidative stress, following infection or injury to the tissue [2,3,4]. This biological response includes physiological adaptations that are elicited to eliminate pathogens and initiate wound healing [5]. Inflammation involves a complex array of functional responses in a cascade of steps [14], involving inflammatory cytokines and other chemical mediators, including prostaglandin [15]. COX enzymes are important targets for non-steroidal anti-inflammatory drugs (NSAIDs) [18]

Methods

Results

Conclusion