Bioanalytical strategies in drug discovery and development

Thakur, Aarzoo; Tan, Zhiyuan; Kameyama, Tsubasa; El‐Khateeb, Eman; Nagpal, Shakti; Malone, Stephanie; Jamwal, Rohitash; Nwabufo, Chukwunonso K

doi:10.1080/03602532.2021.1959606

Cited by 10 publications

(3 citation statements)

References 156 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The translation of these compounds from bench to bedside is primarily dependent on their ability to demonstrate sufficient clinical efficacy and safety profile. Drug metabolizing enzymes and membrane-associated drug transporters are important modulators of the efficacy and safety profile of drugs and their effect on the disposition of these potential neuroprotective agents should be investigated at the early discovery stage to avoid costly clinical development failures [ 195 – 197 ].…”

Section: Management Of Parkinson’s Diseasementioning

confidence: 99%

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Nwabufo

Aigbogun

2022

J Neurol

Self Cite

View full text Add to dashboard Cite

The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson’s disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson’s disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson’s. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson’s and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson’s disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson’s disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson’s disease.

show abstract

Section: Management Of Parkinson’s Diseasementioning

confidence: 99%

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Nwabufo

Aigbogun

2022

J Neurol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Since moving a candidate treatment through the process of approval by the US Food and Drug Administration (FDA) is risky ( Zhong et al, 2018 ), often taking many years, and requiring a substantial financial investment; researchers have expanded their development efforts to drug repurposing ( Hernandez et al, 2017 ; Parvathaneni et al, 2019 ). Traditional methods of drug discovery have involved using low- or high-throughput screens to identify inhibitors or activators of a given target ( Thakur et al, 2021 ; Olgen, 2019 ; Glanz et al, 2020 ). Hits that are identified in these screens are generally optimized prior to subsequent testing in cell culture, animal models, and clinical trials ( Thakur et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Traditional methods of drug discovery have involved using low- or high-throughput screens to identify inhibitors or activators of a given target ( Thakur et al, 2021 ; Olgen, 2019 ; Glanz et al, 2020 ). Hits that are identified in these screens are generally optimized prior to subsequent testing in cell culture, animal models, and clinical trials ( Thakur et al, 2021 ). Alternatively, using a pathway-based approach to drug discovery involves performing experiments to better understand the underlying mechanism(s) of a given condition, and to identify relevant targets ( Deng et al, 2020 ; Wang et al, 2020b ; Damale et al, 2020 ; Chatterjee et al, 2022 ; Liu et al, 2021 ; Ren et al, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

Pathway2Targets: an open-source pathway-based approach to repurpose therapeutic drugs and prioritize human targets

Dobbs Spendlove,

M. Gibson,

McCain

et al. 2023

PeerJ

View full text Add to dashboard Cite

Background Recent efforts to repurpose existing drugs to different indications have been accompanied by a number of computational methods, which incorporate protein-protein interaction networks and signaling pathways, to aid with prioritizing existing targets and/or drugs. However, many of these existing methods are focused on integrating additional data that are only available for a small subset of diseases or conditions. Methods We have designed and implemented a new R-based open-source target prioritization and repurposing method that integrates both canonical intracellular signaling information from five public pathway databases and target information from public sources including OpenTargets.org. The Pathway2Targets algorithm takes a list of significant pathways as input, then retrieves and integrates public data for all targets within those pathways for a given condition. It also incorporates a weighting scheme that is customizable by the user to support a variety of use cases including target prioritization, drug repurposing, and identifying novel targets that are biologically relevant for a different indication. Results As a proof of concept, we applied this algorithm to a public colorectal cancer RNA-sequencing dataset with 144 case and control samples. Our analysis identified 430 targets and ~700 unique drugs based on differential gene expression and signaling pathway enrichment. We found that our highest-ranked predicted targets were significantly enriched in targets with FDA-approved therapeutics for colorectal cancer (p-value < 0.025) that included EGFR, VEGFA, and PTGS2. Interestingly, there was no statistically significant enrichment of targets for other cancers in this same list suggesting high specificity of the results. We also adjusted the weighting scheme to prioritize more novel targets for CRC. This second analysis revealed epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), and two mitogen-activated protein kinases (MAPK14 and MAPK3). These observations suggest that our open-source method with a customizable weighting scheme can accurately prioritize targets that are specific and relevant to the disease or condition of interest, as well as targets that are at earlier stages of development. We anticipate that this method will complement other approaches to repurpose drugs for a variety of indications, which can contribute to the improvement of the quality of life and overall health of such patients.

show abstract

Pharmacokinetics and Pharmacodynamics: Fundamentals and Role(s) in Drug Discovery and Development

Mittal,

Ghai,

Srivastava

et al. 2023

Recent Advances in Pharmaceutical Innovation and Research

View full text Add to dashboard Cite

Bioanalytical strategies in drug discovery and development

Cited by 10 publications

References 156 publications

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson’s disease

Pathway2Targets: an open-source pathway-based approach to repurpose therapeutic drugs and prioritize human targets

Pharmacokinetics and Pharmacodynamics: Fundamentals and Role(s) in Drug Discovery and Development

Contact Info

Product

Resources

About