Computational study on the molecular interactions of tramadol with selected antioxidant and detoxification enzymes in Drosophila melanogaster

Olawole Yakubu Adeniran Olawole Yakubu Adeniran

doi:10.30574/gscbps.2021.15.3.0147

Abstract

Tramadol is a potent analgesic medication prescribed worldwide for treatment of acute and chronic pains. Its relative tendency to be abused has become a public health concern. This study was designed to evaluate the molecular interactions of tramadol with selected antioxidant and detoxification enzymes of Drosophila melanogaster. The structures of CYP2D6, catalase and defense repressor 1 were retrieved from protein database (PubMed, Swiss model) while tramadol 2D structure was obtained from PubChem repository and prepared using LigPrep scripts as implemented in Small-Molecule Drug Discovery Suite of Schrödinger. 2D structure of tramadol was docked into the protein model binding site using Glide software from Schrodinger. The result revealed that, on the binding pocket of CYP2D6, tramadol and CYP2D6 inhibitor bind the protein pocket via hydrogen bond. The hydroxyl group of tramadol and the inhibitor interacts with the C=O groups of the residues Glu 128 and Lys 264 on the protein pocket respectively. Tramadol binds with higher affinity with a docking score of -4.581 kcal/mol when compared with the inhibitor which gave a docking score of -1.865 kcal/mol. With catalase, tramadol and the crystalized ligands were observed to exhibit hydrogen bonding with Ala 64 residue on the protein binding pocket with docking score of -2.348 kcal/mol and -3.431 kcal/mol respectively. The ability of tramadol to interact with these enzymes, strongly suggests that tramadol treatment may induce oxidative stress and at high dose might result in cellular toxicity. Therefore, the toxic effects of tramadol should be of concern despite the important role it plays in pain management.

Highlights

Addiction is an increasing social and health problem worldwide despite all efforts to prevent and control it
The interaction profile reveals that the crystalized ligand binds to a pocket of the protein defined by Ala 64, Phe 68, and Lys 67 via H-bond
Previous finding proposes that the accumulation of regressed forks or supercoiled DNA is responsible for the toxic effects of camptothecin [30]

Summary

Introduction

Addiction is an increasing social and health problem worldwide despite all efforts to prevent and control it. The abuse liability of naturally occurring opiates (e.g., morphine, codeine) and synthetic opioids (e.g tramadol, heroin, oxycodone, and buprenorphine) are well documented in the literatures [2, 3]. Tramadol is a centrally acting analgesic agent that is structurally related to morphine and codeine that is believed to naturally occur in Nauclea latifolia [4]. Addicts abuse tramadol every day by using the drug without doctor prescriptions. In the USA and Europe, according to Hawton et al [6], there have been an upsurge in tramadol use following withdrawal of dextropropoxyphene from the market raising the risk of increased poisonings and deaths attributed to this drug. In Nigeria, the rate of tramadol abuse has been on the increase among Nigerian youths in recent time [7]. Tramadol in the liver is converted to O-desmethyl-tramadol by cytochrome P450 which itself is an active substance and is two to four times

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