High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases

Abstract

Neurodegenerative diseases (NDDs) are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells in the central nervous system (CNS). Identification of viable therapeutic targets and new treatments for CNS disorders and in particular, for NDDs is a major challenge in the field of drug discovery. These difficulties can be attributed to the diversity of cells involved, extreme complexity of the neural circuits, the limited capacity for tissue regeneration, and our incomplete understanding of the underlying pathological processes. Drug discovery is a complex and multidisciplinary process. The screening attrition rate in current drug discovery protocols mean that only one viable drug may arise from millions of screened compounds resulting in the need to improve discovery technologies and protocols to address the multiple causes of attrition. This has identified the need to screen larger libraries where the use of efficient high-throughput screening (HTS) becomes key in the discovery process. HTS can investigate hundreds of thousands of compounds per day. However, if fewer compounds could be screened without compromising the probability of success, the cost and time would be largely reduced. To that end, recent advances in computer-aided design, in silico libraries, and molecular docking software combined with the upscaling of cell-based platforms have evolved to improve screening efficiency with higher predictability and clinical applicability. We review, here, the increasing role of HTS in contemporary drug discovery processes, in particular for NDDs, and evaluate the criteria underlying its successful application. We also discuss the requirement of HTS for novel NDD therapies and examine the major current challenges in validating new drug targets and developing new treatments for NDDs.

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

“…Three-dimensional culture techniques based on the generation of organoids derived from induced pluripotent stem cells, developed in recent years, may be of great value in advancing the generation of biohybrid devices to evaluate new therapeutic alternatives, furthering the understanding of molecular transport mechanisms, and providing an individualized model to simulate conditions close to those that could be found in actual patient tissue [ 53 , 54 ]. High-throughput screening (HTS) techniques can be a complementary tool, as well as assays based on cells and biochemical techniques such as those described by Aldewachi et al [ 55 ] in 2021 and by Pérez del Palacio et al [ 56 ] in 2016, which are necessary and fundamental for analyzing the potential of possible drugs.…”

Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils

“…The methods used for this, namely atomic force microscopy (AFM) [ 35 ] and Fourier-transform infrared spectroscopy (FTIR) [ 37 ], are difficult to apply in situations, where a large number of samples have to be differentiated. In recent years, both high-throughput screening platforms [ 38 ] and computer-aided molecule design systems [ 39 ] have advanced enough to identify neurodegenerative-disease related protein–ligand interactions and possible mechanisms of fibril formation. However, since protein aggregation is still not fully understood, such methods are not ideal for determining the highly complex structure of fully formed aggregates.…”

Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

“…In vivo selections mainly target the vascular system, presenting both disease-altered targets and unaffected molecules. Although, other useful methodologies for target identification and validation exist and have been tested in neurodegenerative and inflammatory conditions [ 19 ], such as high-throughput screening, which is advantageous when little is known of a target, allowing the assay and screening of a large number of biological effectors and modulators against designated and exclusive targets [ 20 ]. The screening and elimination of common peptide ligands has resulted in the discovery of peptide binding inflammatory specific targets [ 17 ] using a phage-displayed library of 12 peptides to select those bound to blood vessels in the CNS parenchyma of rats with experimental autoimmune encephalomyelitis (EAE) [ 17 ].…”