Rational drug discovery design approaches for treating Parkinson’s disease

Abstract

Largely due to the intertwined etiology that is a hallmark of PD's pathology, neuroprotective drug discovery is challenging, while very limited targeting strategies exist for the non-motor symptoms that afflict sufferers of PD. Rational approaches toward PD neurotherapeutics should target previously identified or emerging pathological pathways that are discovered in the course of investigating the underlying mechanisms in PD disease progression. Each of these pathways contributes to events that ultimately lead to the complex disease burden seen in PD and can form the basis for rational and highly targeted drug development.

The “Long and Winding Road” of the Disease‐Modifying Effects of Levodopa Has Not Ended Yet

“…A common hypothesis to develop neuroprotective therapies for PD is that such interventions should interfere with a cascade of molecular events leading to neuronal death. Based on this concept, different mechanisms have been identified as potential targets to promote neuroprotection in PD, including for example neuroinflammation, oxidative stress, excitotoxicity, aberrant calcium (Ca 2+ ) homeostasis, mitochondrial dysfunction, proteosomal dysfunction, α‐synuclein misfolding, and apoptosis among others . From a pharmacological mechanistic standpoint, levodopa (associated with a decarboxylase inhibitor) has a basic and apparently simple and straightforward modus operandi : as a precursor, it increases the level of dopamine in the striatum where it is lacking, thus inducing the spectacular positive short‐term improvement of most motor (and some nonmotor) symptoms of patients with PD.…”

“…Based on this concept, different mechanisms have been identified as potential targets to promote neuroprotection in PD, including for example neuroinflammation, oxidative stress, excitotoxicity, aberrant calcium (Ca 2+ ) homeostasis, mitochondrial dysfunction, proteosomal dysfunction, α-synuclein misfolding, and apoptosis among others. [3][4][5] From a pharmacological mechanistic standpoint, levodopa (associated with a decarboxylase inhibitor) has a basic and apparently simple and straightforward modus operandi: as a precursor, it increases the level of dopamine in the striatum where it is lacking, thus inducing the spectacular positive short-term improvement of most motor (and some nonmotor) symptoms of patients with PD. Nevertheless, the effects of levodopa in PD are far more complex than such a simplistic assumption, indirectly via dopamine transformation or interplay with other neurotransmitters such as noradrenaline, and directly as the drug may exert specific intrinsic actions independently of dopamine transmission.…”

Systemic QSAR and phenotypic virtual screening: chasing butterflies in drug discovery

“…First, our target disease is PD, a multifactorial and multigenic disease of unknown etiology, which constitutes a perfect fit to a complex disease [76] that can benefit from a systemic approach [77]. The selected phenotype was neuroprotection because it is the most realistic and studied disease-modifying therapeutic mode of action in PD [77].…”

“…The selected phenotype was neuroprotection because it is the most realistic and studied disease-modifying therapeutic mode of action in PD [77]. We inspected the literature to locate a reliable source that could provide ligands fitting the selected disease and phenotype.…”

Challenges in detecting disease modification in Parkinson's disease clinical trials

“…This review will consider methodological issues relating to detecting efficacy in disease modification phase III trials and suggest future directions that are being explored that may improve the ability to detect any signal of effect. Earlier stages in drug development and clinical trials present their own specific challenges and these will not be addressed (see [4,5] for review).…”