Computer-Aided Drug Design Applied To Parkinson Targets

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Current Neuropharmacology, 2018, 16, 865-880 865
REVIEW ARTICLE
Computer-aided Drug Design Applied to Parkinson Targets
Hamilton M. Ishiki1, José Maria Barbosa Filho2, Marcelo S. da Silva2, Marcus T. Scotti2 and
Luciana Scotti2,*
1
University of Western São Paulo (Unoeste), Presidente Prudente, SP, Brazil; 2Federal University of Paraíba, Campus
I, João Pessoa-PB, Brazil
Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder

characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines,
changes in affect and sleep disturbances. Although the scientific community has performed great
efforts in the study of PD, and from the most diverse points of view, the disease remains incurable.
The exact mechanism underlying its progression is unclear, but oxidative stress, mitochondrial
dysfunction and inflammation are thought to play major roles in the etiology.
A R T I C L E H I S T O R Y Objective: Current pharmacological therapies for the treatment of Parkinson’s disease are mostly
inadequate, and new therapeutic agents are much needed.
Received: April 05, 2017
Revised: November 24, 2017
Accepted: November 24, 2017
Methods: In this review, recent advances in computer-aided drug design for the rational design of
new compounds against Parkinson disease; using methods such as Quantitative Structure-Activity
DOI:
10.2174/1570159X15666171128145423 Relationships (QSAR), molecular docking, molecular dynamics and pharmacophore modeling are
discussed.
Results: In this review, four targets were selected: the enzyme monoamine oxidase, dopamine
agonists, acetylcholine receptors, and adenosine receptors.
Conclusion: Computer aided-drug design enables the creation of theoretical models that can be
used in a large database to virtually screen for and identify novel candidate molecules.
Keywords: Parkinson’s disease, QSAR, monoamine oxidase, dopamine agonists, acetylcholine receptors, and adenosine
receptors.
1. INTRODUCTION mechanism underlying this process is unclear, but oxidative

stress, mitochondrial dysfunction and inflammation are
Parkinson’s disease (PD) is the second most frequent
thought to play major roles in the etiology [8].
neurodegenerative disorder [1, 2] after Alzheimer’s (AD). PD
can cause significant disability and decreases the quality of Non-motor symptoms can also be observed, and involve
life; clinical manifestations include tremor, rigidity, postural autonomic functions, sleep, cognition, mood and attention
instability and bradykinesia [3]. As an example, PD patients [3], these symptoms can occur across all stages of PD, and
carry a six-fold increased risk for dementia compared to the have been recognized as a key determinant factor for quality
general population, with approximately 80% of patients of life in PD patients [9].
developing dementia over the course of the disease [4].
Presently, there are neither medical treatments nor
Motor ability disruption in PD is due to decreased striatal convincing neuroprotective agents to cure PD. Yet, there are
dopamine levels, arising from selective and progressive loss a number of strategies that help to improve dopamine
of dopaminergic cells within the substantia nigra pars deficiency and therefore PD symptoms [7]. Treatment
compacta and formation of α-synuclein proteinaceous intra- strategies depend on several factors, including patient
neuronal inclusions referred to as Lewy bodies and Lewy disability level, age of the patient, the desire to avoid
neurites [5, 6]. These nigrostriatal circuits are an integral part response fluctuations, potential medication side effects, and
of a complex basal ganglia network and are thought to be affordability [10]. Motor symptoms that result from PD may
involved in a variety of complex functions [7]. The exact be treated with dopaminergic agents, and with functional
neurosurgery, yet the currently available treatments typically
fail to treat non-motor symptoms [11]. Non-motor symptoms
*Address correspondence to this author at the Health Sciences Center,
Federal University of Paraíba, Campus I, 58051-970, João Pessoa-PB,
and non-motor fluctuations can be minimized with
Brazil; Fax: 55-83-3291-1528; E-mail: luciana.scotti@gmail.com dopaminergic treatment or with deep brain stimulation, and
1570-159X/18 $58.00+.00 ©2018 Bentham Science Publishers

866 Current Neuropharmacology, 2018, Vol. 16, No. 6 Ishiki et al.
the dopaminergic pathophysiology of such non-motor includes D1 (or D1a), D5 (D1b), D1c, and D1d [D1a (D1) and D1b
symptoms, likely involves brain areas other than the (D5) these being the principal ones], while the D2-like group
nigrostriatal system [12]. of receptors contains D2L, D2S, D3, and D4 (or D2aL, D2aS, D2b,
and D2c) [22].
The main strategy in the treatment of PD is dopamine
replacement using carbidopa, levodopa, dopamine agonists, Receptors belonging to the family of GPCRs have in
monoamine oxidase type B inhibitors, catechol-o-methyl- common a characteristic 7-transmembrane helix, each of
trfdansferase inhibitors, anticholinergics and amantadine which has 22-28 hydrophobic amino acids [20]. According
[13]. Levodopa has been the therapeutic mainstay for to Sidhu and Niznik [23], the signal pathways involving
patients with idiopathic Parkinson’s disease since the late central dopamine receptors are extremely complicated,
1960’s and continues to be the primary treatment for considering that each of them can interact with more than
management of symptomatic PD [14]. On the other hand, one G protein. This leads to competitive activation in
dopamine agonists cause hallucinations, sleepiness and multiple directions. Dopaminergic system disorders are
compulsive behaviors such as: gambling, hyper-sexuality associated with Parkinson's disease, schizophrenia, mania
and excessive eating [15]. Other side effects of synthetic PD and depression, among others [21, 24].
medications include ankle edema, diarrhea, dry mouth,
Using CoMFA (Comparative Molecular Field Analysis)
tremor, dyskinesia, cognitive impairments and urinary
[25] and CoMSIA (Comparative Molecular Similarity
retraction.
Indices Analysis) [26] analyses, Modi et al. [27] studied the
When a drug therapy fails to successfully manage PD, structural requirements of D2 and D3 receptor ligands for
surgical treatments are recommended. However, the surgery binding affinity, and selectivity for D3 receptors (Fig. 1).
for PD is not devoid of risks. It has been reported that The D3 receptor was chosen; considering its predominant
surgery may increase morbidity and mortality as a result of limbic location in the central nervous system and
intracellular hemorrhages, and thermolytic lesioning of expectations that it would cause fewer undesirable side
structures adjacent to the target sites [16]. effects [24, 28].
Although efforts continue to study PD from the most To derive the 3D QSAR models, 45 structurally diverse
diverse points of view, the disease remains incurable. molecules in a dataset were selected by SAR studies focused
Consequently, the major objective is to design new and more mainly on optimization of the linker length, and the
potent compounds for targets associated with PD. Many arylpiperazine moiety. After the linker length identifications
molecular modeling methods and chemical informatics and possible arylpiperazine moieties, the agonist portion of
techniques have been applied to differing targets in the study the molecule was varied. In this work, two different
of PD. This review aims to examine a reasonable selection of alignment methods, atom-based, and flexible, were tried.
QSAR analyses employed to develop drugs for PD, that
Different training and test sets were used, since
include DA agonists, monoamine oxidase type B (MAO-B)
experimental activity varied significantly for D2, and D3;
inhibitors, levodopa or levodopa plus dopa-decarboxylase
and selectivity between (D2/D3). The training sets were
inhibitors (DDC-I) and catechol-O-methyl transferase
formed by carefully selecting 37 molecules that generated
(COMT) inhibitors.
statistically significant CoMFA models. The remaining
2. DOPAMINE AGONISTS compounds (8) were used as the test set.
Dopamine is an abundant neurotransmitter in the brain, The best CoMFA model for D2, obtained using flexible
and plays an important role as a regulator of many alignment and AM1 charges, gave an rCV2 of 0.713 (4
physiological functions in the central nervous system. These components), a conventional r2 of 0.920, and a standard error
functions include motor activity, cognition and positive of estimate (SEE) of 0.234. The predictive capability was
reinforcement. Additionally, in the periphery dopamine acts rpred2 of 0.926. For the dopamine D3 receptor binding
as a modulator of the cardiovascular and renal functions, affinity, the best CoMFA model, obtained using a flexible
among others [17]. In two steps that occur in the cytosol, alignment and Gasteiger–Hückel charges, gave an rcv2 of
dopamine is synthesized from the amino acid tyrosine. The 0.453 (5 components), an rCV2 of 0.941, a SEE of 0.169 and
first step involves hydroxylation of tyrosine to l- an rpred2 of 0.710. The steric field described 41.5% and
dihydroxyphenylanaline (l-dopa). This reaction is catalyzed 63.6% of variance for the dopamine D2 and D3 binding
by the enzyme tyrosine hydroxylase and requires oxygen. affinities, respectively, and the corresponding contributions
The second step is the decarboxylation of l-dopa to from the electrostatic field were found to be 58.5% and
dopamine. This reaction is catalyzed by the aromatic amino 36.4%, respectively. The mean rcv2 values of 0.731 and 0.472
acid enzyme decarboxylase, and generates CO2 [18]. obtained for the D2 and D3 binding affinities indicated that
the derived models had good internal predictivity. The authors
Dopamine receptors belong to a superfamily of G-protein- suggest that the greater contribution of the electrostatic field
coupled receptors (GPCRs) and have been subdivided into may indicate the importance of the ‘solvation–desolvation’
two groups based on pharmacological behavior [19]. D1 and processes that are crucial for the observed differences in the
D5 receptors are members of the D1-like family of dopamine D2/D3 receptor binding affinities.
receptors and have in common the activation of the enzyme
adenylate cyclase. D2, D3 and D4 receptors are members of The CoMSIA models were generated using five fields:
the D2-like family and characterized by inhibition of steric, electrostatics, hydrophobic, hydrogen bond - donor
adenylyl cyclase [20, 21]. The D1-like group of receptors and acceptor. Initially, the analyses were performed using
Computer-aided Drug Design Applied to Parkinson Targets Current Neuropharmacology, 2018, Vol. 16, No. 6 867
OH
Ar2 Ph
N N
Ar H
N N
N N
H
Fig. (1). Molecular structures of the derivatives used in the 3D QSAR studies.
individual fields as well as various combinations of the illustrates a graphic representation of the 3D-pharmacophore
different fields. For D2 binding affinity, the CoMSIA model, embedded in the 4D-QSAR model using Compound 5-((1-
using atom-based alignment and AM1 charges, obtained an (4-fluorophenyl)-3-[4-[[(2R,3aR,12bS)-11-fluoro-3,3a,8,12b-
rcv2 of 0.719 (4 components), rconv2 of 0.912, SEE of 0.245 tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan-2-
and rpred2 of 0.911. For D3 binding affinity, the best model yl]methyl]-1-piperazinyl]-1-propanone) as a reference [17].
using flexible alignment and Gasteiger–Hückel charges
pIC50 = +7.418 + 2.493(3,9,3,any) + 2.592(4,9,0,np) +
obtained an rcv2 of 0.493 (6 components), an rconv2 of 0.898, a
3.697(7,12,0,any) –1.261(5,7,4,any) + 1.323(2,5,4,any) –
SEE of 0.227 with an rpred2 of 0.465. Removal of compound
3.028(4,6,3,np) – 4,285(5,12,3,any) –2.173(9,9,3,any) +
33 (an outlier) improved the rpred2 value from 0.465 to 0.640.
Once more, the derived models showed good internal 4.437(3,8,1,np) Eq (1)
predictivity considering the mean rcv2 values of 0.726 and n=60, r2 = 0.759, r2adj = 0.716, q2 = 0.668, q2adj = 0.616, LSE
0.456, respectively for D2 and D3. = 0.051, LOF = 0.098
The CoMFA-generated plots revealed good correlation
between the steric and electrostatic fields and the binding
potencies at the D2, D3 receptors, and selectivity at D3
(D2/D3), with a dominating contribution made by the steric
field on the electrostatic counterpart (for D3 and D2/D3), or
vice versa (for D2). The models obtained revealed the
importance of the carbonyl group, (which is likely involved in
potential H-bonding interactions with the D3 target residues),
and a biphenyl substituent, as important determinants for the
D3 selectivity of the studied compounds.
Silva et al. [17] have performed 4D-QSAR analysis using
73 compounds from tetracyclic tetrahydrofuran derivatives
containing a cyclic amine side chain in the 2-position (Fig. 2),
and with binding affinity towards dopamine D2 receptors;
related to locomotor activity [20]. From the compounds, 60
were selected from the literature [29] to be employed in the
training set and the remaining 13 compounds, randomly Fig. (3). Compound 5 with descriptors derived from the best
selected from the original set, were employed as test set to QSAR-4D model.
validate the model. The negative logarithm of the
concentration capable of inhibiting 50% of human D2L The positive coefficients observed in Equation 1 for the
activity (pIC50 =- logIC50) was used as biological activity. grid cell occupancy descriptors (GCODs) (3,9,3,any),
The conformational ensemble profile of each ligand was (4,9,0,np) (7,12,0,any), (2,5,4,any), (3,8,1,np) indicate
constructed using molecular dynamic simulation. Calculations favorable interactions between the substituent molecule and
were done in order to model solvent effect in the absence of amino acid residues in the D2 active site. This indicates that
explicit solvent [30]. substituents in these positions increase the potency of the
N compounds. On the other hand, the negative coefficients
observed for (5,7,4,any), (4,6,3,np), (5,12,3,any), (9,9,3,any),
O
indicate unfavorable interactions between the substituent
molecule and amino acid residues in the D2 active site,
which indicates that substituents in these positions will
F
decrease the potency of the compounds.
Further, GCODs (2,5,4, any), (3,9,3,any), (4,6,3,np) and
Fig. (2). Molecular structure of the dopamine D2 receptor derivatives. (5,7,4, any) situated near the cyclic amine, will implicate the
group’s relative orientation as important for increasing/
The leave-one-out cross-validation analysis of the best decreasing biological activity. GCODs (2,5,4, any) and
model resulted in a q2 value of 0.668 with a standard error of (3,9,3, any) may represent interactions, such as salt bridges,
0.263 which indicates a predictive capacity of 67% between the piperazyl moiety and amino acid Asp114.
(Equation 1). The optimum number of latent variables (PLS GCODs (3,8,1,np) and (4,9,0,np) are related to nonpolar
components), used for further analysis was seven. Fig. (3) interactions and are located close to hydrogen atoms. In
summary, hydrophobic substituents attached to the piperazyl phenyl ring have a favorable effect on biological activity.
ring contribute to increase biological activity and a The hydrophobic volume maps suggested that hydrophobic
hydrophilic substituent at (9,9,3,any) position will increase interactions at the 4-position of the aromatic ring increase
biological activity. biological activity. The electron-withdrawing volume maps
suggested that the presence of a methoxy group at the 2-
A set of 45 novel illoperidone analogs, 3- position of the aromatic ring decreases biological activity,
[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazole (Fig. 4), for
and the presence of a carbonyl group at the 4-position
D2 antagonism, as selected from the literature [31], were
increases biological activity.
studied by Dash et al. [32], using 3D-QSAR approach. In
this study, the pharmacophore and 3D-QSAR modeling was Active compounds were docked with the 3D structure of
carried out using PHASE software [33]. This software the D2 receptor using Glide XP docking. The results suggest
identifies common spatial arrangements between functional that H-bond donor hydroxyl groups attached to the 2-
groups which are essential to biological activity, considering position of the aromatic ring increase biological activity, and
a set of high-affinity ligands. PHASE software provides a that hydrophobic benzisoxazole ring interactions occur with
standard set of pharmacophore features: hydrogen-bond amino acids VAL79, ILE148, VAL154, PHE353, PHE354
donor, hydrogen-bond acceptor, negatively ionizable, positively and ILE358. Inhibitor piperidine rings display hydrophobic
ionizable, hydrophobic group, and aromatic ring. The interaction with VAL75, TRP350 and PHE375, and inhibitor
1/logIC50 value for D2 inhibition was used as a biological hydrophobic chains interact with aromatic residues of
activity parameter. PHE74, TYR372, PHE375 and TYR380.
[ X In the final step, an in silico screening search for novel
N ]n R 2
D2 antagonists was performed considering all four
R1 pharmacophoric features, obtaining 4,171 hits in the Zinc
N
O database. The hits having fitness scores of less than 80%
were discarded, and 119 compounds were further selected
Fig. (4). The structure of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzis-
for cluster analysis. Taking into account the predicted value
oxazole derivatives.
of 1/logIC50 greater than 0.411, 86 hits were chosen for
In the first step, the conformational space of all the Glide SP docking onto the active site of D2 receptor, and 11
molecules was explored through a combination of Monte- hits, with XP GlideScore ≤ −8.5, were considered to be
Carlo multiple minimum/low mode sampling with maximum potential D2 inhibitors.
number of 2,500 conformers per structure and 100
The sumary of dopamine agonist studies is presented in
minimization steps [34]. A pharmacophore model based on
Table 1.
common molecular features was generated and validated by
3D-QSAR analysis. 45 compounds were divided into a 3. MONOAMINE OXIDASE
training set (34 compounds), and a test set (11 compounds)
for the purpose of atom-based 3D-QSAR. Monoamine oxidase (MAO) is a flavo-protein, localized
2 in the mitochondrial outer membrane, that catalyzes
The training set resulted in the following PLS factors (R oxidative deamination of biogenic and xenobiotic amines.
= 0.925, SD = 0.045, F = 69.8, P = 6.281e-015), and the test The enzyme has essential functions in the metabolism of
set was characterized by the following PLS factors (Q2 = neuro-active and vasoactive amines in the central nervous
0.756, RMSE = 0.107, Pearson-R = 0.907). system and peripheral tissues [35]. MAO degrades dopamine
Resulting from the 3D-QSAR approach, the H-bond excesses in the cytosol, catalyzing oxidative deamination of
donor map suggested that the presence of a primary amine the dopamine amino group to 3,4-dihydroxyphenylace-
and hydroxyl group near the 2- and 5- positions of the taldehyde with concomitant formation of ammonia and
Table 1. Main results obtained for dopamine agonists by computer-aided drug design methods.
Authors Compound Principal Results
Modi et al. [27] arylpiperazine derivatives - ‘solvation–desolvation’ processes are crucial for the observed differences in the D2/D3
receptor binding affinities;
- the carbonyl group and a biphenyl substituent, are determinants for the D3 selectivity.
Silva et al. [17] tetracyclic tetrahydrofuran - hydrophobic substituents attached to the piperazyl ring;
derivatives - hydrophilic substituent at (9,9,3,any) position will increase biological activity.
Dash et al. [32] Illoperidone derivatives - primary amine and hydroxyl group near the 2- and 5- positions of the phenyl ring;
- hydrophobic interactions at the 4-position of the aromatic ring and
- the presence of a carbonyl group at the 4-position will increases biological activity.
- a methoxy group at the 2-position of the aromatic ring decreases biological activity.
hydrogen peroxide. The product of this reaction is then

metabolized by the enzyme aldehyde dehydrogenase to 3,4-
dihydroxyphenylacetic acid using NAD as an electron
donator [18].
Two MAO isoforms can be found in all mammals, MAO-A
and MAO-B. The difference between these isoforms is based
on their respective substrate preferences, their sensitivities to
the acetylenic inhibitors clorgyline and L-deprenyl
(selegiline), and by their tissue distribution [35-37]. MAO-A
has higher affinity for serotonin, dopamine, norepinephrine
and epinephrine whereas high affinity substrates of MAO-B
include tyramine, phenylethylamine and MPTP [38-40].
MAO-A, is found in the gastrointestinal tract [37] and
plays a role maintaining low cytosolic concentrations of
dopamine. It has been suggested that MAO-A plays a role in
oxidative stress because the enzyme generates hydrogen
peroxide [41]. MAO-B is found in the human brain, where it
acts in the breakdown of dopamine and in deamination of
phenylethylamine. This amine is responsible for stimulating
the release of dopamine and inhibits its neuronal reuptake
[42]. With aging, expression levels of MAO-B in neuronal
tissue enhance 4-fold, increasing dopamine metabolism
levels, and production of dopanal and hydrogen peroxide.
The increase in hydrogen peroxide promotes apoptotic
signaling events resulting in decreased levels of dopamine-
Fig. (5). Mechanism of action of the selective nigral toxin 1-
producing cells, which play a key role in neurodegenerative
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
diseases such as Parkinson’s and Alzheimer’s [43]. For these
reasons, pharmacologists have focused attention on the
development of MAO-B inhibitor drugs [44]. [53], were studied by Hasegawa et al. [54] through QSAR
analysis. The first biological activity was in vitro MAO
McNaught et al. [45] described the destruction of the inhibitory activity. Other three biological activities were in
dopamine-containing neurons of the substantia nigra pars vivo MAO inhibitory activities within respective noradrener-
compacta in PD, which may be related to the mechanism of gic (NA), dopaminergic (DA), and serotonergic (5-HT)
action of the selective nigral toxin 1-methyl-4-phenyl- neurons of the rat brain. The activity was expressed as the
1,2,3,6-tetrahydropyridine (MPTP) (Fig. 5). In brain, the negative logarithm of the 50% inhibitory concentration
toxin MPTP is metabolized by glial MAO-B to produce its (pIC50).
active metabolite 1-methyl-4-phenylpyridinium (MPP+) [46,
47]. Prior to its energy-dependent concentration within The relationship between MAO inhibitory activity and
mitochondria, MPP+ is actively accumulated by dopaminergic structural descriptors was analyzed using the nonlinear PLS
neurons via the dopamine reuptake system [47-49]. MPP+ method. Principal component analysis (PCA) was also
induces cell death by selective inhibition of NADH employed to verify similarities and differences among the
ubiquinone reductase (complex I) and α-KGDH resulting in four MAO biological activities.
ATP depletion [50-52]. NH2
McNaught et al. [45] considering that isoquinoline
derivatives are structurally related to MPTP or MPP+, and
may be endogenous neurotoxins contributing to cell death in Fig. (6). Chemical structure of phenyl alkylamines derivatives.
PD, studied substrate affinities of 14 neutral and quaternary
isoquinoline derivatives for their ability to inhibit the uptake Two significant components were obtained when PCA
of [3H] dopamine into rat striatal synaptosomes in the analysis was employed on the dataset. The first explained
dopamine reuptake system. Using the selected compounds, 83.7% of the total variance in the conventional and cross-
QSAR and 3D-QSAR produced no statistically acceptable validated steps, and the second explained 82.1%. The
model. However, certain favorable or unfavorable functional loading plot of first against the second principal component
group regions helped to contribute to the molecular modeling showed that four biological activities were clustered into two
analyses. Thus, a 2-methyl group in 1,2,3,4-tetrahydro- groups, in vitro (biological variable 1) and in vivo MAO
isoquinoline or a 7-methoxy group increased activity, inhibitory activities (biological variables 2, 3 and 4).
whereas two -OH substituents in positions 6- and 7- were
notably unfavorable for activity. Hasegawa et al. [54] performed the PLS analysis
separately. The MAO in vitro activity PLS model resulted in
Twenty phenyl alkylamine derivatives (Fig. 6), taken R2 values of 0.988 and Q2 values of 0.861. The PLS models
from literature, all having four MAO inhibitory activities, developed for the three in vivo MAO inhibitory activities
resulted on R2 values of 0.863 (NA), 0.897 (DA), and 0.855 rotatable single bonds can be found in both selective and
(5-HT) and Q2 values of 0.576 (NA), 0.511 (DA), and 0.595 non-selective molecules.
(5-HT).
The molecular descriptors: average molecular weight
The QSAR analysis performed for the in vitro MAO (AMW), Geary autocorrelation - lag 3 / weighted by atomic
inhibitory activity demonstrated that such activity is favored polarizabilities (GAT3p), and descriptors calculated from the
by large, electron-withdrawing and hydrophobic substituents eigenvalues of a modified distance adjacency matrix graph,
at ortho positions. Meta positions were not significant. weighted with partial charges (GCUT_PEOE_2) also
Electron-donating substituents at para positions increased appeared in the results with a high frequency. The authors
biological activity. Considering the analysis performed for in suggest that results coming from further descriptor analyses
vivo MAO inhibitory activity, the QSAR analyses demonstrated may provide useful knowledge towards hMAO-B selective
that electron-withdrawing substituents at ortho positions and inhibitor design [81].
electron-donating substituents at para positions increase
Pisani et al. [82] performed 3D-QSAR and docking
biological activity. Substituents at meta positions are limited
simulations on a series of 7-metahalobenzyloxy-2H-
by small steric volume.
chromen-2-one derivatives (Fig. 7), considering their rat
Helguera et al. [55] performed QSAR analysis to a set of monoamine oxidase A and B inhibition activity. The data of
over 450 different types of heterocyclic compounds, such as a series of MAO inhibitors was obtained in house [83]. The
chromones, homo-isoflavonoids, coumarins, and their initial series, with 67 compounds, was split into a training set
precursors (chalcones), 2-hydrazinylthiazoles, and pyrazoles. (58 compounds) and a test set (9 compounds), having similar
The compounds were obtained both in house [56-58], and coverage in terms of biological activity, range, and structural
from the literature [59-76], and then evaluated for human diversity. Biological activity towards MAO-B was
MAO in a single and consistent inhibition assay [77]. associated via Partial Least Squares to the variation of
Considering that the data set contains stereoisomers, which electrostatic, steric, hydrophobic, hydrogen bond acceptor,
cannot be distinguished by 2D descriptors, the authors and hydrogen bond donor fields using the Gaussian-based
discarded one. In this way, data set was formed by 449 fields available in Phase [33].
organic compounds. R2
The compounds were classified into four groups
considering the IC50 and pSI values, where pSI is selectivity
R1
to hMAO-B. They were divided into training and test sets to O O O
obtain validated QSAR models. The descriptors used in this
work were available in the DRAGON [78], MOE [79] and
MODESLAB [80] software. Linear Discriminant Analysis Fig. (7). Chemical structure of coumarin derivatives.
was employed to find classification models that best
described biological activity, as a linear combination of The obtained 3D-QSAR model revealed robust statistics
predictor descriptors. for both sets: training (n = 58, r2 = 0.856, RMSE = 0.421,
stability = 0.853, factors = 4, q2 = 0.605), and test (n = 9, r2ext
The three descriptor sets used in combination with the = 0.794, RMSE = 0.457). The steric field contributes with
Linear Discriminant Analysis classification method revealed 32.10% to the model; the hydrophobic field contributes
that DRAGON and MOE descriptors-derived models 25.80%, the electrostatic contributes 23.30%, the hydrogen
displayed higher predictive powers than those using the bond donor contributes 12.60% and the hydrogen bond
TOPS-MODE approach. The most frequent shape-related acceptor contributes 6.20%. The existence of a larger
descriptors were associated with van der Waals volumes or forbidden steric region bound to position 4 decreases MAO-
areas (i.e. MATS3v, PEOE_VSA+1 and Q_VSA_FNEG), B inhibitory activity. Electron rich substituents at the meta
and with self-returning walk count of order 5 (SRW05). The position of the 7-benzyloxy substituent increase MAO-B
SRW05 descriptor is related to the presence of five member activity, and the occurrence of hydrogen bond donor
rings in the chemical structure. This result is in agreement interactions increase MAO-B inhibition. From the
with previous SAR results that describe decreases in potency computational analysis it was observed that most of the
and selectivity for hMAO-B activity when simultaneous examined coumarin derivatives exhibited a very high and
substituents are present in position 3- and 5- of the selective inhibition of MAO B.
pyrazoline ring [70].
Considering these characteristics, a new series of MAO
The most frequent descriptor based on the counting of inhibitors were designed and prepared. In this new series,
atom-centered fragments was the C-019, and the descriptors substituents at position 4 were introduced with unhindered
based on the chemical functional groups were nArCO and hydrophilic groups exhibiting hydrogen bond donor/acceptor
nCrs, and (b_1rotN) bonds. The descriptor (C-019) describes properties. In the low nanomolar range these 4,7-substituted
the =CRX fragment, where R represents any group linked coumarin derivatives showed outstanding MOA-B selectivity
through carbon; X represents any electronegative atom and = for the MAO-A isoform, and for MAO-B inhibitory potencies.
represents a double bond. It was observed that this fragment
is mostly included in non-selective ligands. The descriptors: The resume of monoamine oxidade inhibitors studies are
nArCO representing aromatic ketones, nCrs representing the presented in Table 2.
number of secondary rings C(sp3), and b_1rotN representing
Table 2. Main results obtained for monoamine oxidade inhibitors.
McNaught et al. isoquinoline derivatives - 2-methyl group and;

[45] -7-methoxy group will increase biological activity.
-OH substituents in positions 6- and 7- will decrease biological activity.
Hasegawa et al. phenyl alkylamine derivatives - at ortho positions, large, electron-withdrawing and hydrophobic substituents and;
[54] - at para positions, electron-donating substituents will increase biological activity.
Helguera et al. heterocyclic compounds, such as - van der Waals volumes or areas and five member rings are important to the biological activity.
[55] chromones, homo-isoflavonoids, - substituents in position 3- and 5- of the pyrazoline ring will decrease biological activity.
coumarins, and their precursors
Pisani et al. [82] 7-metahalobenzyloxy-2H- - larger steric region bound to position 4 decreases MAO-B inhibitory activity. - electron rich
chromen-2-one derivatives substituents at the meta position of the 7-benzyloxy substituent increase MAO-B activity,
-4,7-substituted showed outstanding MOA-B selectivity for the MAO-A isoform.
4. ACETHYLCHOLINE RECEPTORS combinations of α2, β, γ, δ and ε subunits [84]. These

nAChRs play a key role in signal transmission between cells
The endogenous cholinergic neurotransmitter, acetylcholine,
at the nerve/muscle synapses [89] and in neurodegenerative
exerts its biological effect via two types of cholinergic
pathologies [90, 91]. In the central nervous system, subunits
receptors: muscarinic acetylcholine receptors (mAChRs),
α2–α7 and β2–β4 combine in a variety of different
and nicotinic acetylcholine receptors (nAChRs). These two
stoichiometries, resulting in the formation of receptors with
types of receptors are different in both structure and function. distinct biological functions [92]. The α4β2 subtype is the
The muscarinic acetylcholine receptors belong to a most widespread heteromeric nAChR subtype in the central
class I subfamily of hepta-helical, trans-membrane G-protein nervous system (CNS), involved in memory, drug addiction
coupled receptors (GPCRs) and were discovered from their and excitement [93].
ability to bind to the alkaloid muscarine. Muscarinic receptor
Reduction in nAChR activity is a dysfunction in a variety of
subtypes were initially classified pharmacologically as
neurological and psychiatric disorders such as Alzheimer’s,
either M1 or M2 based on their differential sensitivity to Parkinson’s, schizophrenia, hyperactivity, depression and
pirenzepine, a selective antagonist to the M1 receptor [84].
even nociception [94-97]. Thus, pharmaceuticals that
Today, they are divided into five distinct subtypes, denoted
selectively target nAChRs might be valuable for the
as M1, M2, M3, M4 and M5 [85].
treatment of behavioral symptoms in PD [98].
Muscarinic M1, M3 and M5 receptors couple preferentially
In order to find out the chemical features modulating
to the Gq/11 subunit type of G-proteins, activating phos-
affinity to nAChRs, Nicolotti et al. [99] initially performed a
pholipase C-β, and inducing a subsequent increase in 2-D QSAR analysis for the different congeneric series of
intracellular calcium concentration [86]. On the other hand,
nicotinic agonists separately. From the literature, 269
M2 and M4 couple mainly to Gi/o G-proteins, and typically
nAChR ligands were taken containing several different
lead to adenylate cyclase inhibition, with activation of
series namely: i) nicotine, phenylpyrrolidine, isonicotine and
inward-rectifier potassium conductance [87].
3-aminomethylpyridine derivatives [100-104] (Fig. 8a), ii)
Nicotinic acetylcholine receptors derive their name from (hetero)aryloxymethylazacyclic derivatives [105-107] (Fig.
their affinity for nicotine and are largely distributed both in 8b), iii) arecolone and isoarecolone derivatives [108] (Fig.
the peripheral and central nervous systems [88]. Nicotine 8c), and iv) nitrogen polycyclic derivatives [100, 109-113]
binds directly to the receptor α subunit and stimulates the (Fig. 8d) with various core structures.
opening of a nonspecific cation channel formed by various
R3
N R6 R2 R4 N R2 N R6
R`
3
H
+
R`4 R5 R `1 N
+ R`2
N+H N+ H R N R4
R`5 R1 `
R1 H
(A ) (B ) (C ) (D )
Fig. (8a). Chemical structures of (A) nicotinoid agonists, (B) phenylpyrrolidine derivatives, (C) isonicotine derivatives and (D) 3-
aminomethylpyridine derivatives.
R3
R2 N R6 R2 N R6 R2 R4
O R5 O R5 ( )n X R5
N+ R` R4 N+ R4 N+ `
1
H R1 R1
H H
(A ) (B ) (C )
Fig. (8b). Chemical structures of (A) pyridyloxymethylpyrrolidine derivatives, (B) pyridyloxymethylazetidine derivatives and (C)
phenoxymethylazacyclic derivatives.
R O The steric effects at positions 1, 3, 4 and 5, of nicotine

O
ligands, can be quantitatively valued by comparing the
R negative coefficients with MR in equation 2.
+ +
N N pKi = 9.05 (0.64) - 1.17 (0.39) MR1’ - 1.81 (0.85) MR3’ -
H CH 3 H CH 3 1.06 (0.44) MR4’ - 0.97 (0.29) MR5’ Eq (2)
(A ) (B )
n=28 r2=0.731 (q2=0.572) s=0.480
Fig. (8c). Chemical structures of (A) arecolone and (B)
isoarecolone derivatives. The lipophilic effect, represented by π, can be observed
with equation 3.
The binding mode of the nAChR agonists was also pKi = 10.32 (0.45) + 1.45 (0.26) π- 1.33(0.19)B5 Eq (3)
investigated at the 3-D level by the standard CoMFA [25]
procedure, and the GRID/GOLPE approach [114-116], with n=15 r =0.831 (q =0.713) s=0.538
the lipophilic DRY probe was applied. The 3-D QSAR analyses allowed merging of all
The 2-D QSAR analysis of the congeneric series of congeneric series with development a global model with
nicotinoid analogs showed that two main effects influence good predictive ability. The arecolone and isoarecolone
ligand binding at the nAChR. Steric effects are unfavorable series, the 3-isoxazole derivatives, and the three non-
for biological activity, and lipophilic effects are favorable to pyrrolidine compounds were combined to form a unique
biological activity. These observations were found for all molecular database. The full set of ligands was split into a
classes of examined compounds, and were related to the bulk training set, consisting of 206 compounds, and an evaluation
parameter; Molar Refractivity (MR) and the STERIMOL set, consisting of 34 compounds. The good correlation
parameter B5. In three cases the STERIMOL parameter B5 between the binding affinities as calculated for the training
steric descriptor was correlated with better pKi values than set model, and those observed was obtained. Thus, proving
MR. the predictivity of the 3-D QSAR model generated. As
N R R O
N N
O
N
+N H 2 +N H
H2N +
R +
H N
+ H N
R
R
N N
N O N
R + H
N
H 2N +
+ +
N H N
H CH 3
R
N
O N O N
+
N
+ H
N CH
3 R
H H
Fig. (8d). Chemical structures of nitrogen polycyclic derivatives.

observed in 2-D QSAR results, the models derived mostly located around the protonated nitrogen. The introduction of
showed the prevalent effects of steric features. substituents or bulky ring systems, which have unfavorable
interactions with the C3 probe, increases biological activity.
Nielsen et al. [117] synthesized six novel series of potent
The coefficient plot for the OH2 probe differs from that for
ligands with nanomolar affinity for the α4β2 nAChR
the C3 probe in the 6-position (and 5-position) of the
subtype, which is the major subtype found in brain tissue. pyridine ring. The results indicate that substituents with
The affinities of the compounds for the α4β2 subtype of
unfavorable electrostatic interactions with the water probe
nAChRs have been investigated in vitro using [3H]cytisine
increase biological activity. Tønder et al. [121] published a
binding to rat cerebral cortical membranes. The 3D-QSAR
pharmacophore model with similar results.
model was based on a training set of 25 compounds, and a
test set composed of 4 compounds. All calculations were The resume of acetylcholine receptors studies are
evaluated using the GRID [114, 118] and GOLPE [116, 119, presented in Table 3.
120] 3D-QSAR approach. The compounds were aligned using
(R)-epibatidine and the conformationally restricted nicotinic 5. ADENOSINE RECEPTORS
analogue 29 as templates (Fig. 9).
Adenosine acts as an endogenous modulator in both the
HN central and peripheral nervous systems by interacting with
NH
four transmembrane G protein coupled receptors (GPCRs)
identified as adenosine receptors (ARs) A1, A2A, A2B, and A3
H [122, 123] (Fig. 10). ARs (A1 and A3) are negatively coupled
C l N to adenylyl cyclase and exert an inhibitory effect on cyclic
N
adenosine monophosphate (cAMP) production [123].
(A ) (B ) Adenosine A1 receptors inhibit adenylate cyclase activity.
Activation of these receptors results in the opening of several
Fig. (9). Structures of (A) (R)-epibatidine, and (B) compound 29 types of potassium channels, and closing of certain calcium
employed as templates for the alignment step. channels. The adenosine A3 receptors are not as well-
understood as the others. Receptor stimulation leads to the
The GRID was used to calculate the interaction energies
formation of inositol triphosphate (IPA3), and consequently,
between the compounds and the four probes (OH2, C3, O-,
to increased calcium concentration in the cell [124].
and N1+) in order to mimic possible interactions with the
receptor. The final model was obtained using only two
probes: OH2 and C3, considering that the N1+ probe
reduced the predictivity of the model dramatically, and the
O- probe had coefficient plots similar to the plots for the
OH2 probe.
The smart region definition (SRD) and the fractional
factorial design (FFD) selection in GOLPE were applied to
eliminate the noise variables. The SRD variable pre-selection
reduced the number of variables from 15.155 to 2.169
without altering the quality of the model (Q2 = 0.390). The
FFD variable selection reduced the number of variables to
983 with a highly significant improvement in the quality of
the model, with Q2 from 0.38 to 0.81.
The coefficient plots for the OH2 probe and for the C3
Fig. (10). Adenosine receptors.
probe showed some identical regions. The identical regions
with highest negative values were located around the 6- ARs (A2A and A2B) stimulate adenylyl cyclase activity,
position on the pyridine ring, and to a lesser extent around inducing cAMP level increases in cells [125]. Both subtypes
the 5-position. The negative coefficients indicate that bulk differ in location and pharmacological properties. In the CNS,
substituents in these positions reduce biological activity. The adenosine A2B receptor is widely spread, yet adenosine A2A
identical regions having the highest positive values are receptors are found only in dopaminergic regions of the
Table 3. Main results obtained for acetylcholine receptors.
Nicolotti et al. [99] nicotinic agonists - steric effects are unfavorable for biological activity;
- lipophilic effects are favorable to biological activity.
Nielsen et al. [117] pyridines derivatives - bulk substituents around the 6-position and to a lesser extent around the 5-
position will decrease the biological activity.
brain [124]. Adenosine A1 and A2A receptors are unknown member is predicted from the activity of a certain
characterized by high affinity for adenosine, while A2B and number (k) of nearest neighbors (kNNs) in the training subset.
A3 receptors show significantly lower affinity for adenosine. To validate the kNN-QSAR selected pharmacophores,
operating characteristic curve (ROC) analysis was employed.
Adenosine A2A receptors are primarily expressed in
Such analysis makes it possible to assess the ability to
dopamine rich areas of the CNS [126], and are located on the selectively capture diverse Adenosine A2A antagonists from a
bodies of indirect pathway medium spiny striatal neurons
large list of decoys [130].
and dopamine terminals. Currently, connections between A2A
and D2 receptors are of great interest for Parkinson’s disease The successful pharmacophores were complemented with
(PD) treatment, which involves a decrease in dopamine exclusion spheres to improve their ROC receiver profiles.
levels [127]. The best QSAR models were used as 3D search queries to
perform a virtual screen in the National Cancer Institute
Antagonism of AR (A2A) reduces adenosine signaling, structural database, to identify novel Adenosine A2A
enhances the sensitivity of the dopaminergic neurons, and
antagonist leads. The most potent hit yielded an IC50 value of
restores balance to the signaling pathway controlling muscle
545.7 nM.
movement. Thus, an A2A receptor antagonist may be a
beneficial monotherapy for the treatment of PD and could be Using 3D-QSAR, molecular dynamics, and thermodynamic
a very interesting target in new drug design. There has been analysis, Zhang et al. [131] studied the interactions of 278
a significant effort over the past decade to synthesize novel monocyclic and bicyclic pyrimidine derivatives with the
and selective A2A receptor antagonists, and as result, human A2A adenosine receptor. The compounds were
istradefylline (KW-6002) was launched under the name classified and separated artificially into three sets, i.e.,
Nouriast as the first antiparkinsonian agent based on A2A Training set I: pyrimidine and triazine derivatives (97
receptor antagonism [128]. compounds); Training set II: pyrazolo[3,4-d]pyrimidines,
pyrrolo[2,3- d]pyrimidines, triazolo[4,5-d]pyrimidines and
Khanfar et al. [129] employed a genetic function
6-arylpurines (120 compounds); and Training set III:
algorithm (GFA) to build predictive QSAR models for a thieno[3,2-d]pyrimidines (61 compounds) (Fig. 11). Two
collection of 188 Adenosine A2A antagonists in order to
kinds of alignment were performed: i) the most active
generate differing pharmacophore binding hypotheses. The
compound in each dataset was considered as template and
GFA method was employed to select differing combinations
the Align-Database function in Sybyl [25] was executed, and
of pharmacophores and molecular descriptors. The phar-
ii) the bioactive conformations of all compounds were at
macophoric space of Adenosine A2A antagonists was
once derived from docking, and then processed, using the
explored through eight HYPOGEN automatic runs that were initial method.
performed on seven training subsets. Compounds in the
training subsets were selected considering structural diversity Docking analysis was performed to verify binding sites
and a wide range of bioactivities. The training subsets were of wild AR [A2A (PDB code 3PWH.pdb)] with certain
chosen considering that differences in Adenosine A2A mutations (PDB code 3EMS.pdb). To mimic the impacts of
bioactivity primarily results from the presence or absence of receptor flexibility, and water solvation effects on the ligand-
pharmacophoric features. receptor complex, a dynamic simulation was carried out.
Analysis of the docking results showed that the binding
In this work, Khanfar et al. [129] implemented the
poses for the three kinds of the derivatives maintained
genetic function algorithm as a tool for selecting differing
similar binding modes within the AR (A2A).
combinations of pharmacophores and molecular descriptors.
The ability of the resulting pharmacophore(s)/descriptor(s) Interactions between ligands and the active AR (A2A) site
combinations to explain biological activity variations was involves polar interactions with GLU169 and ASN253 side
explored using two methodologies: (a) multiple linear chains, non-polar interactions with VAL84, LEU249,
regression (MLR) analysis, and (b) kNN regression. MET270 and ILE274, and π-stacking between aromatic
moieties of the ligands and the conserved PHE168 side chain
Unfortunately, the QSAR predictive models obtained by
of the receptor. The docking results showed that ASN253 is
using GFA/MLR-based QSAR analyses were statistically
capable of forming stable H-bonding with ligands. This
insignificant. In order to improve the results, kNN-based
indicates that the residue is fundamental in maintaining
QSAR analysis was employed. This approach relies on a
binding poses with different heterocyclic compounds. After
distance learning methodology, where the activity of an docking, the energetically favorable conformations from
Ra Ra Ra
Rd 6 6 6
X 5 S 5
5 X A N1 Y B A 1
N
A
N
1
Rc 4 N 2 Rb N 4 N 2 Rb 4 N 2 Rb
3 Re 3 3
(A) (B) (C)
Fig. (11). Structures of (A) pyrimidine and triazine derivatives (X=C/N), model I; (B) pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-
d]pyrimidines, triazolo[4,5-d]pyrimidines and 6-arylpurines derivatives (X=C/N and Y=C/N), model II and (C) thieno[3,2-d]pyrimidines
derivatives, model III.
among the compounds were selected for CoMFA and thermodynamic, structural descriptors and charge dependent
CoMSIA modeling. descriptors.
Several molecular descriptors were included in the PLS The physicochemical screening of 4-arylthieno [3, 2-d]
analyses to derive more reasonable QSAR models. All of the pyrimidine derivatives was executed using FAF-Drugs [134].
statistical parameters obtained using the CoMFA and This tool performs various physicochemical calculations,
CoMSIA approaches were reasonably high, which confirms identifies key functional groups, certain toxic, and unstable
the stability and predictability of the models. Three models molecules or functional groups.
were generated.
The QSAR model was generated using respectively 19
The maps of model I show that bulky groups at C4 and and 21 4-arylthieno [3, 2-d] pyrimidine derivative compounds
C6 positions on the pyrimidine ring increase binding affinity. as training sets for A1 and A2A inhibitors. The best models
Bulky groups near substituents at C2, C5 and C6 positions are presented in equations 4 and 5. The QSAR models were
decrease binding affinity. The upper region of the group at generated using the genetic function approximation (GFA).
C4 is favorable for hydrophobic interaction. Interactions This algorithm is a useful technique for a database with a
between the ligands may occur with ALA63, ILE66 and large number of descriptors and a small number of
ILE274. Hydrophilic groups at C2 and C4 increase binding molecules. In this step, only 37 compounds were analyzed,
affinities. At C2, a small, electronegative and hydrophilic considering their poor scalability.
substituent would increase binding activity. To increase the
binding affinity, a limitedly bulky group at C4 should bear A1 = 23.4694 + 0.701334 ∗ (DIPOLE MAG) − 2.7753 ∗
(CHI-V-3-P) Eq (4)
both electronegativity and hydrophilic interactions but not in
the role of H-bond donor. Non-H groups at C5 such as n=19, r2 =0.77, r2adj=0.752, LOF=0.808, q2=0.662.
methyl would decrease inhibitory activity.
A2A = 73.649 − 1.2009 ∗ (SC − 2) − 0.248049 ∗ (AREA) +
The maps of model II indicate that at C6 of the 0.10049 ∗ (WIENER) − 0.0014297 ∗ (PHI-MAG);
pyrimidine ring, a minor electronegative group should play a Eq (5)
role as H-bond acceptor and increase biological activity. At
C2 of the pyrimidine ring, an H-bond donating group n=21, r2 =0.936, r2adj=0.913, LOF=0.668, q2=0.881.
increases biological activity as can be observed for The predictive ability of the QSAR model was further
compounds substituted with an amino group at this position. validated with the test set containing 12 compounds for A1,
At Nitrogen at position 3 of ring B, N3, a limitedly bulky and 12 compounds for A2A inhibitors. The r2 values of the A 1
group as H-bond acceptor increases biological activity. An and A2A antagonists were above 0.7, indicating a good
aromatic ring attached to the nitrogen is essential for both percentage of total variance in biological activity. The q2 >
affinity and selectivity for A2A antagonists. 0.6 suggested that the models will be useful in the future for
In the maps of model III at position C6 of the pyrimidine meaningful predictions. Validation was done employing test
ring, electronegative, hydrophilic and limited bulky groups sets that contained 12 compounds of A1 and A2A inhibitors.
as H-bond donors increase inhibitory activity. At position C2 The predictive power of the model was reasonably good with
of the pyrimidine ring, a small and electronegative group as predictive r2 values (0.961, 0.914), and cross validated r 2
H-bond donor is well tolerated and would functionally being respectively (0.912, and 0.781).
deliver good potency. At position C2, a small lipophilic For equation 7, the DIPOLE MAG descriptor suggests that
group plays an important role in AR (A2A) affinity and the strength and behavior of the molecule’s orientation will
selectivity over AR (A1). increase A1 inhibitory activity. The molecular connectivity
A series of 4-arylthieno[3, 2-d] pyrimidine derivatives was index CHI-V-3-P suggests that molecular bonds, clusters,
studied by Ahmed et al. [132] through QSAR analysis in rings and flexibility are less favored for A1 inhibitory
order to evaluate antagonist activity towards both adenosine activity.
A1 and adenosine A2A targets (Fig. 11). Biological data of For equation 8, the topological descriptor SC-2 suggests
adenosine A1 and adenosine A2A for QSAR analysis was unfavorable molecular branching for inhibition activity. The
obtained from the literature [133]. The structures of 4- molecular surface area (AREA) describes binding, transport,
arylthieno [3, 2-d] pyrimidine derivatives, Fig. (12), were and solubility for a molecule; and the negative weight
built using INSIGHT-II (Accelrys Software Inc., US) suggests a less favorable inhibition of the A2A receptor. The
software. The Cerius2 package was used to calculate the Wiener graph–theoretical descriptor represents the sum of
molecular descriptors, which included: 2D topological, the chemical bonds existing between all pairs of heavy atoms
S N S
R R1
S S S S
N N N N
N R N Et N R N R
C al ss -A C al ss -B C al ss -C C al ss -D
Fig. (12). Structures of 4-arylthieno [3, 2-d] pyrimidine derivatives.

Table 4. Main results obtained for adenosine receptors by computer-aided drug design methods.
Zhang et monocyclic and Model I

al. [131] bicyclic pyrimidine - at C4 on the pyrimidine ring hydrophilic and bulky groups and;
derivatives
- at C6 bulky groups will increase binding affinity;
- upper region of the group C4 hydrophobic interaction are favorable;
- at C2, a small, electronegative and hydrophilic substituent will increase binding activity.
- at C5 and C6 bulky groups will decrease binding affinity;
- at C5 non-H groups will decrease inhibitory activity.
Model II
- at C6 a minor electronegative group should play a role as H-bond acceptor and iwill ncrease biological activity;
- at N3 of ring B a limitedly bulky group as H-bond acceptor will increase biological activity;
- an aromatic ring attached to the nitrogen is essential for both affinity and selectivity for A2A antagonists.
Model III
- at C6 electronegative, hydrophilic and limited bulky groups as H-bond donors will increase inhibitory activity;
- at C2 a small lipophilic group plays an important role in AR (A2A) affinity and selectivity over AR (A1).
Ahmed et 4-arylthieno[3, 2-d] - the strength and behavior of the molecule’s orientation will increase A1 inhibitory activity;
al. [132] pyrimidine - molecular bonds, clusters, rings and flexibility are less favored for A1 inhibitory activity;
derivatives
- molecular branching will decrease the biological activity;
- binding, transport, and solubility and the negative weight suggests a less favorable inhibition of the A2A receptor;
- the increase in the number of heavy atom pairs will increase the biological activity;
- less flexibility for the compounds will enhance A2A receptor inhibition.
in the molecule. The positive value suggests that increases in results presented in this review may help the development of
the number of heavy atom pairs in the molecules increases new drugs against Parkinson's disease and promote its cure.
inhibitory potency. Finally, the negative weight of the PHI-
MAG descriptor suggests less flexibility for 4-arylthieno [3, CONSENT FOR PUBLICATION
2-d] pyrimidine derivatives in enhanced A2A receptor
Not applicable.
inhibition.
The resume of adenosine receptors studies are presented CONFLICT OF INTEREST
in Table 4. The authors declare no conflict of interest, financial or
CONCLUSION otherwise.
Application of computational methods is of great ACKNOWLEDGEMENTS
importance to drug discovery, and methods such as Declared none.
molecular docking, QSAR, pharmacophore modeling and
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Computer-aided Drug Design Applied to Parkinson Targets

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder

1. INTRODUCTION mechanism underlying this process is unclear, but oxidative

1570-159X/18 $58.00+.00 ©2018 Bentham Science Publishers

Authors Compound Principal Results

hydrogen peroxide. The product of this reaction is then

Table 2. Main results obtained for monoamine oxidade inhibitors.

Authors Compound Principal Results

McNaught et al. isoquinoline derivatives - 2-methyl group and;

4. ACETHYLCHOLINE RECEPTORS combinations of α2, β, γ, δ and ε subunits [84]. These

R O The steric effects at positions 1, 3, 4 and 5, of nicotine

Fig. (8d). Chemical structures of nitrogen polycyclic derivatives.

Table 3. Main results obtained for acetylcholine receptors.

Authors Compound Principal Results

Fig. (12). Structures of 4-arylthieno [3, 2-d] pyrimidine derivatives.

Authors Compound Principal Results

Zhang et monocyclic and Model I

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