Screening Libraries for Parkinson’s Disease

Expert-driven In Silico Drug Discovery Solutions
18 August 2020
Andrew Golub
Group Leader, Molecular Design

A neurodegenerative disorder called Parkinson's disease (PD) affects mainly dopamine-producing (“dopaminergic”) neurons in a specific area of the brain (“substantia nigra”). Symptoms of PD usually develop slowly over a long time. Due to the diversity of PD, the progression of its symptoms may vary significantly from one person to another. So far very little has been known about the cause of PD. Treatment options vary and include medications and surgery, although there is no cure for this disease.

Discovery of novel drugs capable of stopping or slowing down the progression of neurodegenerative symptoms still remains a task to be solved.

The World Brain Day 2020 is a good opportunity to spotlight the whole range of issues and challenges associated with Parkinson’s disease.

parkinson's desease

About a century ago, Friedrich Lewy made a fundamental discovery towards the understanding of PD by identifying and describing large cytoplasmic proteinaceous inclusions in the brains of patients who had died of the disease [1]. These inclusions, subsequently termed Lewy bodies, were different in their morphology and location from those found in other neurodegenerative disorders, e.g., extracellular amyloid plaques of Alzheimer's and intranuclear inclusions of Huntington's disease [2]. Their preferential location in the regions most affected in Parkinson's, including those within surviving dopaminergic neurons of the pars compacta, firmly established Lewy bodies as one of the critical neural substrates of Parkinson's disease. It remains controversial whether Lewy bodies are harmful to neurons or they produce only a protective response. However, seminal pathological studies in the 1980s found that the majority contained a small protein, ubiquitin, discovered in the preceding decade and shown to be a critical modifier that tagged proteins for degradation [3]. Therefore, the identification of ubiquitin in Lewy bodies provided strong evidence for the role of altered ubiquitin signaling and disrupted protein quality control in Parkinson's disease. However, the molecular insights into how ubiquitin controlled these processes, including essential enzymes involved in mediating ubiquitylation, the identification of key ubiquitylated substrates that reside in inclusions, and the crucial components controlling the reverse pathway remained unknown [4].

Biochemical alterations found in the brains of Parkinson's disease patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signaling and kinase or ligase cascade play a central role in protein quality control [5-8].

Joining World Brain Day 2020, Life Chemicals provides a selection of potential inhibitors and targeted libraries for research in the area related to Parkinson’s disease treatment:

Representative compounds and their analogs from the Life Chemicals Stock HTS Compound Collection tested against Parkinson’s disease  

Figure 1. Representative compounds and their analogs from the Life Chemicals Stock HTS Compound Collection tested against Parkinson’s disease (according to López Cara LC, Camacho ME, Carrión MD, et al. 2009)

 

References:

  1. Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013;9(1):13-24. 
  2. Yerbury JJ, Ooi L, Dillin A, et al. Walking the tightrope: proteostasis and neurodegenerative disease. J Neurochem. 2016;137(4):489-505.
  3. Goldstein G, Scheid M, Hammerling U, Schlesinger DH, Niall HD, Boyse EA. Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc Natl Acad Sci U S A. 1975;72(1):11-15. 
  4. Walden H, Muqit MM. Ubiquitin and Parkinson's disease through the looking glass of genetics. Biochem J. 2017;474(9):1439-1451.
  5. López Cara LC, Camacho ME, Carrión MD, et al. Phenylpyrrole derivatives as neural and inducible nitric oxide synthase (nNOS and iNOS) inhibitors. European Journal of Medicinal Chemistry. 2009 Jun;44(6):2655-2666.
  6. Cookson MR. Structure, function, and leucine-rich repeat kinase 2: On the importance of reproducibility in understanding Parkinson's disease. Proc Natl Acad Sci U S A. 2016;113(30):8346-8348.
  7. García AM, Redondo M, Martinez A, Gil C. Phosphodiesterase 10 inhibitors: new disease-modifying drugs for Parkinson's disease?. Curr Med Chem. 2014;21(10):1171-1187.
  8. Mehdi SJ, Rosas-Hernandez H, Cuevas E, et al. Protein Kinases and Parkinson's Disease. Int J Mol Sci. 2016;17(9):1585.
18 August 2020, 10:16 Andrew Golub Computational Chemistry

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