Challenges and Discoveries in Polypharmacology of Neurodegenerative Diseases

Abstract

Background: Neurological disorders are composed of several diseases that affect the central and peripheral nervous system; among these are neurodegenerative diseases, which lead to neuronal death. Many of these diseases have treatment for the disease and symptoms, leading patients to use several drugs that cause side effects. Introduction: The search for new treatments has led to the investigation of multi-target drugs. Method: This review aimed to investigate in the literature the multi-target effect in neurological disorders through an in silico approach. Studies were reviewed on the diseases such as epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, cerebral ischemia, and Parkinson's disease. Result: As a result, the study emphasize the relevance of research by computational techniques such as quantitative structure-activity relationship (QSAR) prediction models, pharmacokinetic prediction models, molecular docking, and molecular dynamics, besides presenting possible drug candidates with multi-target activity. Conclusion: It was possible to identify several targets with pharmacological activities. Some of these targets had diseases in common such as carbonic anhydrase, acetylcholinesterase, NMDA, and MAO being relevant for possible multi-target approaches.

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

“…75,76 This combination approach provides a very promising strategy, not reported before, meeting the polypharmacology criteria, which seem necessary to deal with neurodegenerative diseases involving several pathophysiological processes. 123 In order to determine the drug-likeness of 13−15 in vitro, an assessment of PK properties was performed. All three compounds presented favorable permeability in the PAMPA and satisfying metabolic stability in rLMs (13, 14) and hLMs (15) models.…”

“…This is especially beneficial in the context of searching for innovative therapies for AD, where oxidative stress plays an essential role in the development of the disease. The introduction of selenium into our 1,3,5-tri­azine-based serotonin-receptor ligands and subsequent optimization toward selective 5-HT 6 R resulted not only in modulating a single target (i.e., 5-HT 6 R) but also in mimicking GPx, which can be highly useful in AD treatment. , This combination approach provides a very promising strategy, not reported before, meeting the polypharmacology criteria, which seem necessary to deal with neurodegenerative diseases involving several pathophysiological processes …”

Polypharmacology: promises and new drugs in 2022

“…At its core (Fig. 1 ) is the assumption that in the case of the treatment of multifactorial diseases, such as multiple sclerosis [ 16 ], Alzheimer’s disease [ 5 , 17 – 19 ], epilepsy [ 20 ], cancer [ 21 ], kidney diseases [ 22 ], infectious diseases [ 23 ], metabolic syndrome [ 24 ] or cardiovascular diseases [ 25 ], simultaneous modulation of different molecular targets that form a network of interconnections by a single molecule is more advantageous than the use of multiple highly specific ligands in polytherapy [ 9 , 10 , 26 , 27 ].

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“…The continuous progress in medical and life sciences, especially within the omics sciences (genomics, proteomics, metabolomics, etc.) gave the perspective for a new strategy for drug design and treatment, which was termed polypharmacology [ 5 – 10 ]. According to the National Library of Medicine (2014), this promising novel concept is defined as the design or use of pharmaceutical agents that act on multiple targets or disease pathways [ 11 ]; this definition is still actual [e.g., 5 – 10 ].…”

“…gave the perspective for a new strategy for drug design and treatment, which was termed polypharmacology [ 5 – 10 ]. According to the National Library of Medicine (2014), this promising novel concept is defined as the design or use of pharmaceutical agents that act on multiple targets or disease pathways [ 11 ]; this definition is still actual [e.g., 5 – 10 ]. However, polypharmacology does not compete with polytherapy and should not be considered as a phenomenon exclusive to well-established practices [ 8 ].…”