In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease

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 antiparkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. 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 phenomena) associated with long-term L-DOPA replacement therapy have limited its antiparkinsonian efficacy. The investigation for non-dopaminergic therapies has been largely explored as an attempt to counteract the motor side effects associated with dopamine replacement therapy. Being one of 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 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 subclasses, 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.

RGS Proteins as Critical Regulators of Motor Function and Their Implications in Parkinson’s Disease

“…G protein-coupled receptors (GPCRs), the largest family of cell-surface receptors encoded by the genome, have provided promising avenues for alternative PD therapies. In particular, animal models of PD have implicated modulation of noradrenergic, cholinergic, adenosinergic, glutamatergic and serotonergic neurotransmission as possible adjunctive therapies to current dopaminergic treatments (reviewed by Lemos et al, 2018). Unfortunately, high levels of conservation in the orthosteric binding site within GPCR subfamilies has limited the development of receptorsubtype specific drugs and thus, like the dopaminergic therapies currently employed in PD, these treatment options would likely have numerous side effects.…”

A Complete Assessment of Dopamine Receptor- Ligand Interactions through Computational Methods

“…Structure-based approaches rely on the availability of the target crystal structure or homologs proteins whereas pharmacophore and other ligand-based methodologies rely on the existence of a sufficient number of ligands. For example, for GPCRs potentially involved in Parkinson’s disease, a variety of molecular docking studies were carried out using resolved crystal structures to which self-synthesized ligands were docked (reviewed in Lemos et al, [34]). Vice versa , inspection of known ligands was used to build pharmacophores or Quantitative Structure-Activity-Relationships (QSAR) to screen for new bioactive molecules (reviewed in Lemos et al, [34]).…”

“…For example, for GPCRs potentially involved in Parkinson’s disease, a variety of molecular docking studies were carried out using resolved crystal structures to which self-synthesized ligands were docked (reviewed in Lemos et al, [34]). Vice versa , inspection of known ligands was used to build pharmacophores or Quantitative Structure-Activity-Relationships (QSAR) to screen for new bioactive molecules (reviewed in Lemos et al, [34]). All in all, CADD is capable of addressing many challenges in hit-to-lead-development and is currently widely used in the pharmaceutical industry [34,35].…”

“…Vice versa , inspection of known ligands was used to build pharmacophores or Quantitative Structure-Activity-Relationships (QSAR) to screen for new bioactive molecules (reviewed in Lemos et al, [34]). All in all, CADD is capable of addressing many challenges in hit-to-lead-development and is currently widely used in the pharmaceutical industry [34,35].…”

Residues and residue pairs of evolutionary importance differentially direct signaling bias of D2 dopamine receptors

“…The D2 dopamine receptor is arguably the GPCR of most pervasive neuropharmacological importance, due to its role in the actions of virtually all psychotropic drugs and in human disorders ranging from substance abuse to Parkinson's disease (2,(15)(16)(17)(18)(19). Recent studies in vivo using either biased drugs selected for preferential activation of one pathway or the other downstream of D2R (20) or D2R variants engineered to trigger ␤-arrestin or G-protein pathways selectively (21), have confirmed that different behavioral effects of D2R-directed drugs act differentially through these two pathways.…”