Neurodegenerative diseases are characterized by progressive degeneration of neurons in the cerebral region. Several factors can lead to this degeneration such as ageing, environmental, and genetic factors [1–3]. NDDs are classified into Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Prion like diseases, and amyotrophic lateral sclerosis [2, 4, 5]. Among which AD and PD are familial as well sporadic type. prevalence of PD is expected to crossover AD if not treated [7–9].
PD is a motor disorder and its onset leads to degeneration of dopamine neurons at the substantia nigra pars compacta, and causes deficiency of a neurotransmitter dopamine. Symptoms like tremors, bradykinesia, akinesia, and postural instability are broad-spectrum [10–11]. The pathogenesis of PD is a complex interplay of oxidative stress and cellular signaling, which results in to mitochondrial damage, neuroinflammation, protein accumulation, autophagy, and so on [12–14]. Presently more than 10 million people are suffering from PD all over the world. Its prevalence is increasing among people of 60 years and above, which is expected to be doubled by 2040[15–16].
Despite decades of research, there is no absolute medication available to treat PD . Current therapies for PD provide relief from the symptoms, although the unavoidable side effects and instability are documented after long-term use [10–12]. Therefore, it is necessary to develop a novel drug for better therapeutic activity to meet the clinical demand.
New drug development cost has exceeded 1 billion US dollar since 2000 and it is rising continuously [18–19]. Hence various artificial intelligence techniques are used in drug discovery to overcome the economic burden, which include target protein structure prediction, drug protein interaction, de novo drug design, and so on . In that scenario in-silico approach or structure based virtual screening has become a potential technique in drug discovery [21, 22].
Drug repositioning is an alternative approach in the enhancement of efficiency of drugs. It identifies new clues for existing drugs, along with predicted drug safety profile [23, 24]. Among several molecules used in drug repositioning Edaravone is one which can be a potential scaffold for other NDDs. It show neuroprotective effect via antioxidant activity . Hence applying repositioning technique, might help in discovery of novel Pyrazolone derivatives for other NDDs.
Mary LC Hare in 1928 discovered mono amino oxidase protein, which are family members of flavin adenine dinucleotide cofactor-dependent enzymes present on the mitochondrial membrane. MAO oxidize variety of amine substrates like small mono-amino molecules, polyamines, and modified protein amino acids . Therefore, MAO plays an important role in modulating monoamine neurotransmitter levels in central and peripheral nervous systems. Dopamine is a neurotransmitter that is oxidized by MAO-B at substantia nigra of basal ganglia. In PD dopamine level in the SNPC region is reduced, and the level of dopamine can be maintained by MAO-B inhibitors. Pyrazolones are also potent inhibitors of the MAO enzyme family, and it is one of the therapeutic pathways used to treat PD, therefore Pyrazolones can be a promising scaffold for the treatment of PD [27, 28].
In this study, we hypothesized that MAO-B inhibition with Pyrazolone derivatives may result in ceasing PD symptoms and possibly it may cure PD. For that purpose, library of compounds was designed and virtually docked for binding efficiency, the ADME predictions were performed by Qikprop analysis, Molecular Mechanics /generalized born surface area analysis was carried out to identify the drug-receptor complex's, binding free energy, and five compounds were selected that fit on all parameters.
The identification of novel MAO-B inhibitors and the study of their inhibitory mechanism will be helpful for the development of possible MAO-B targeting Parkinson’s disease