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Moreira and Cordeiro-MS Send Orders for Reprints to [email protected] 786 Current Neuropharmacology, 2018, 16, 786-848 REVIEW ARTICLE In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease Agostinho Lemosa,b, Rita Meloc,d, Antonio Jose Pretoc, Jose Guilherme Almeidac, Irina Sousa Moreirac,e,* and Maria Natalia Dias Soeiro Cordeiroa,* aLAQV/REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal; bGIGA Cyclotron Research Centre In Vivo Imaging, University of Liège, 4000 Liège, Belgium; cCNC - Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Rua Larga, 3004-517 Coimbra, Portugal; dCentro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (ao km 139,7), 2695-066 Bobadela LRS, Portugal; eBijvoet Center for Biomolecular Research, Faculty of Science - Chemistry, Utrecht University, Utrecht, 3584CH, The Netherlands Abstract: Parkinson’s Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti- parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly de- manding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD. However, the development of dyskinesias and motor fluctuations (wearing-off and on-off phenom- ena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian A R T I C L E H I S T O R Y efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt Received: March 06, 2017 to counteract the motor side effects associated with dopamine replacement therapy. Being one of Revised: February 02, 2018 Accepted: February 16, 2018 the largest cell membrane protein families, G-Protein-Coupled Receptors (GPCRs) have become a relevant target for drug discovery focused on a wide range of therapeutic areas, including Central DOI: 10.2174/1570159X16666180308161642 Nervous System (CNS) diseases. The modulation of specific GPCRs potentially implicated in PD, excluding dopamine receptors, may provide promising non-dopaminergic therapeutic alternatives for symptomatic treatment of PD. In this review, we focused on the impact of specific GPCR sub- classes, including dopamine receptors, adenosine receptors, muscarinic acetylcholine receptors, metabotropic glutamate receptors, and 5-hydroxytryptamine receptors, on the pathophysiology of PD and the importance of structure- and ligand-based in silico approaches for the development of small molecules to target these receptors. Keywords: Parkinson’s disease, G-protein-coupled receptors, drug design, ligand-docking, quantitative structure-activity rela- tionships, pharmacophore. 1. INTRODUCTION most common neurodegenerative disorder after Alzheimer’s Disease (AD), affecting approximately 1% of the population Parkinson’s Disease (PD) was originally described by worldwide over 55 years old. PD has been defined as a pro- James Parkinson, in 1817, as a neurological disturbance con- gressive, irreversible, and chronic neurological disorder sisting of resting tremor and a distinctive form of the characterized by increasingly disabling motor symptoms that progressive motor disorder, designated as shaking palsy or are associated to impaired coordinated movements including paralysis agitans in his monograph entitled An Essay On the bradykinesia (slowness of initiation of voluntary move- Shaking Palsy [1]. Currently, it is considered the second ments), resting tremor, cogwheel rigidity, postural instabil- ity, and gait disorders [2-4]. In addition, the majority of PD patients do not suffer from motor disabilities alone and nu- *Address correspondence to these authors at the LAQV@REQUIMTE/ merous non-motor symptoms may lead to a decrease in the Department of Chemistry and Biochemistry, University of Porto, 4169-007 Porto, Portugal; Fax: +351 220402659; E-mail: [email protected] and CNC quality of life in patients: cognitive impairment, hallucina- - Center for Neuroscience and Cell Biology, Faculty of Medicine, Univer- tions, psychosis, anxiety, and depression [5, 6]. Another fre- sity of Coimbra, Rua Larga, 3004-517 Coimbra, Portugal; Fax: +351 quent anomalies related to autonomic (gastrointestinal and 304502930; E-mail: [email protected] cardiovascular), sensory and Rapid Eye Movement (REM) 1570-159X/18 $58.00+.00 ©2018 Bentham Science Publishers In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Current Neuropharmacology, 2018, Vol. 16, No. 6 787 and sleep behaviour dysfunctions are also clinically mani- tions, such as the troublesome dyskinesias (involuntary mus- fested in PD patients. Despite decades of comprehensive cle movements) [18, 19]. In addition, dopaminergic therapies study and knowledge concerning the etiology and patho- focused on targeting dopamine receptors (DRs) with agonists genesis of PD, much has yet to be discovered in order to have displayed favorable outcomes in early stages of PD, understand the pathophysiological mechanisms that contrib- exhibiting antiparkinsonian effects with the lower risk of ute to the neuronal cell death (neurodegeneration) in PD. occurrence of problematic dyskinesias. DR agonists have Although normal aging represents the most important risk also been used in combination with L-DOPA to delay the factor, a combination of environmental (e.g. exposure to development of motor complications in late stages of the pesticides and herbicides, toxins, and organic solvents) and disease. Nevertheless, the use of DR agonists may result in genetic factors may contribute to the onset of PD [7]. Two non-motor complications (psychiatric disorders, nausea, distinctive pathological manifestations have been associated vomiting, orthostatic hypotension, increased somnolence and to the clinical diagnosis of PD in post-mortem patients, in- sleep attacks, fatigue, and ankle edema) more severe than L- cluding the selective and progressive degeneration of dopa- DOPA. Therefore, the occurrence of motor and non-motor minergic neuromelanin-containing neurons from the Sub- complications associated to all types of dopamine replace- stantia Nigra pars compacta (SNc) of the midbrain and ment therapy suggested that the symptomatic treatment of striatum of the brain and the presence of Lewy bodies, in- PD focused on the re-establishment of dopaminergic neuro- traneuronal inclusions of presynaptic protein α-synuclein in transmission may possess restricted therapeutic benefits for brain neurons [2-6]. patients. Apart from dopaminergic therapies, the modulation of non-dopaminergic neurotransmission systems, including The reduction of dopamine levels and the loss of SNc noradrenergic, cholinergic, adenosinergic, glutamatergic, and dopaminergic neurons have shown to influence directly the serotonergic, has been explored as alternative therapeutic appearance of motor dysfunctions associated to PD in 6- approaches for symptomatic monotherapy and in combina- HydroxyDopamine (6-OHDA)- and 1-Methyl-4-Phenyl- tion with dopaminergic therapies. Interestingly, numerous 1,2,3,6-TetrahydroPyridine (MPTP)-treated animals. Since studies have emphasized the relevance of pharmacological the degree of SNc dopaminergic neurodegeneration corre- modulation of specific G-protein coupled receptors (GPCRs) lates positively with the severity of PD, dopamine replace- for PD symptomatic therapy in preclinical PD animal models ment therapies have become the most effective therapeutic and clinical studies with PD patients. The present review alternative to ameliorate daily function, quality of life, and highlights the impact of specific GPCR subclasses in the survival in PD patients. However, the therapeutic strategy of pathophysiology of PD, the structure-, and the ligand-based direct administration of dopamine itself is not feasible, due in silico approaches widely used in the identification of to their inability to cross the Blood-Brain Barrier (BBB) [8]. small-molecule modulators of these particular receptors. An alternative BBB-permeable dopamine precursor, L-3,4- DihydrOxyPhenylAlanine or levodopa (L-DOPA), was con- 2. G-PROTEIN-COUPLED RECEPTORS AS THERA- ceived to effectively enhance dopamine concentration in the PEUTIC TARGETS FOR PARKINSON’S DISEASE Central Nervous System (CNS). The antiparkinsonian effects of L-DOPA were first described by Carlsson and co-workers With the increasing number of new cases per year of PD, in reserpine-treated animals [9] and, later, in human PD pa- there has been a considerable increase in the search for new tients after intravenous [10] and oral administration of low therapeutic alternatives. While the research and development doses of L-DOPA [11]. Currently, L-DOPA is considered of promising drugs are demanding for all emerging therapeu- the most effective medication for correcting dopamine defi- tic areas, the discovery of new therapeutic agents acting on ciency in PD, significantly attenuating the motor symptoms PD and other CNS diseases has been particularly demanding in human patients. Upon administration to systemic circula- and is associated to a very high attrition rate [20]. GPCRs- tion, L-DOPA is converted
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