Molecular docking investigation of the amantadine binding to the enzymes upregulated or downregulated in Parkinson's disease.

Mihaela Ileana Ionescu

doi:10.5599/admet.854

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease. Levodopa in combination with amantadine has a demonstrated efficacy in motility impairment. An extensive investigation of some enzymes described to be upregulated or downregulated in PD was made – adenylate kinase (AK), adenine phosphoribosyltransferase (APRT), ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), nucleoside-diphosphate kinase 3 (NDK3), purine nucleoside phosphorylase 1 (PNP1), and ecto-5’-nucleotidase (NT5E). Also, creatine kinase (CK) was included in the study because it is one of the main enzymes involved in the regulation of the nucleotide ratio in energy metabolism. To date, there is no proven link between amantadine treatment of PD and these enzymes. Because there are many AKs isoforms modified in PD, the AK was the first investigated. The molecular docking experiments allow the analysis of the selective binding of amantadine – unionized (with –NH2 group) and ionized form (with –NH3+ group) – to the AKs’ isoforms implicated in PD. Using available X-ray 3D structures of human AKs in closed-conformation, it was demonstrated that there are notable differences between the interactions of the two forms of amantadine for the zebrafish AK1 (5XZ2), human AK2 (2C9Y), human AK5 (2BWJ), and AK from B.stearothermophilus. The cytosolic human AK1 and human AK2 mostly interact with ionized amantadine by AMP binding residues. The human AK5 interaction with ionized amantadine does not involve the residues from the catalytic site. Among other enzymes tested in the present study, APRT revealed the best results in respect of binding amantadine ionized form. The results offer a new perspective for further investigation of the connections between amantadine treatment of PD and some enzymes involved in purine metabolism.

Highlights

Parkinson’s disease (PD) is an idiopathic neurodegenerative and progressive disease, which mainly produces motility impairment with bradykinesia, tremor, and postural instability [1,2]
There are nine human adenylate kinase (AK) isoforms described until now, but only those isoforms with X-ray 3D structure solved were further analyzed by molecular docking
The AKs with 3D structure co-crystallized with substrates or analog substrates are optimal for our study because the AK is in closed-conformation, with the flexible LID domain covering the substrate

Summary

Introduction

Parkinson’s disease (PD) is an idiopathic neurodegenerative and progressive disease, which mainly produces motility impairment with bradykinesia, tremor, and postural instability [1,2]. In PD, the neurotransmitter dopamine is reduced as a result of the degeneration of the dopaminergic neurons from the substantia nigra [3]. ADMET & DMPK 8(2) (2020) 149-175 due to the losses/impairment of the dopamine action at the basal ganglions [4,5]. PD is a chronic disease with no curative treatment of the underline disease. The drugs used in the treatment of PD should correct the dopamine/cholinergic balance, because the level of dopamine in the caudateputamen in the striatum is considerably reduced, with the exacerbation of the cholinergic control [15,16]. The most used dopaminergic drugs are levodopa, bromocriptine, and amantadine whereas the main anticholinergic drug is trihexyphenidyl [17,18,19,20]

Results

Discussion

Conclusion