Blood–brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery

Pardridge, William M.

doi:10.1517/14728222.2015.1042364

Cited by 116 publications

(93 citation statements)

References 66 publications

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“…Endothelium allows rapid free diffusion of oxygen from blood to brain and carbon dioxide from brain to blood, which is essential for normal brain metabolism and regulation of pH in the brain ISF, neurons and other NVU cells. Small lipophilic molecules and drugs, with a molecular weight of < 400 Da and form of <8 hydrogen bonds, can cross the BBB (Pardridge, 2015). …”

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

“…At the BBB, the SLC proteins facilitate the transcellular transport of a variety of molecules, including carbohydrates, amino acids, monocarboxylic acids, hormones, fatty acids, nucleotides, organic anions, amines, choline and vitamins (Table 1) (Daneman and Prat, 2015; Pardridge, 2015; Zlokovic, 2008). Human genetic studies have provided important insight into the roles of the more recently characterized SLC transporters in both rare and common diseases.…”

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

“…As discussed below, genetic alterations in brain endothelial SLC2A1 (Glut1) that transports glucose into the brain and maintains the BBB integrity (Winkler et al, 2015) and in SLC16A2 that transports T3 thyroid hormone into the brain have been implicated in the development of neurological disorders (Benarroch, 2014; Kersseboom et al, 2013). Screening for BBB-penetrating small molecules that can use the existing CMT systems at the BBB as surrogate ligands has been recently proposed as a new model for CNS discovery programs (Pardridge, 2015). …”

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

“…However, certain neuroactive peptides (Zlokovic, 1995), regulatory proteins, hormones and growth factors can use RMT systems to slowly cross the BBB (Pardridge, 2015; Zlokovic, 2008) (Table 1). For example, Aβ can cross the BBB to enter the circulation through LRP1 (Deane et al, 2004) or the other way around via the receptor for advanced glycation end products (RAGE) on RAGE-expressing endothelium, particularly under pathological conditions (Deane et al, 2003, 2012).…”

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

See 3 more Smart Citations

Establishment and Dysfunction of the Blood-Brain Barrier

Zhao

Nelson

Betsholtz³

et al. 2015

Cell

1,185

1,128

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Structural and functional brain connectivity, synaptic activity and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit and intact blood-brain barrier (BBB) functions. Here, we examine the mechanisms regulating the formation and maintenance of the BBB and functions of BBB-associated cell types. Furthermore, we discuss the growing evidence associating BBB breakdown with the pathogenesis of inherited monogenic neurological disorders and complex multifactorial diseases including Alzheimer’s disease.

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Section: Cellular Components Of the Bbbmentioning

confidence: 99%

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

Section: Cellular Components Of the Bbbmentioning

confidence: 99%

See 2 more Smart Citations

Establishment and Dysfunction of the Blood-Brain Barrier

Zhao

Nelson

Betsholtz³

et al. 2015

Cell

1,185

1,128

View full text Add to dashboard Cite

show abstract

“…This could be compared to the administration of drugs by smart delivery systems (smart transport) from periphery to the central nervous system of the human body (smart mobility), in order to improve the whole system [23,24].…”

Section: Differences Between Sustainable Mobility and Smart Mobilitymentioning

confidence: 99%

Urban Policies and Mobility Trends in Italian Smart Cities

2017

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This study uses indicators to evaluate the progress made by Italian cities in the smart mobility sector, in order to understand how these cities have approached the new guidelines imposed by the European Union, and how they have implemented the European changes. Specifically, this study analyses the evolution of public transportation systems, using a sample of twenty-two Italian cities for three successive time periods (2005, 2010, and 2015). The outcomes identified are then linked to funding provided for the implementation of projects related to smart mobility in the cities studied, in order to verify possible correlations between the growth of these services and European and national financial investments. The data analysis shows remarkable progress in the field of sustainable mobility, especially between 2010 and 2015 as well as how this progress is linked to significant financial support that favours the realization of projects related to smart mobility.

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Docking, Scoring, and Virtual Screening in Drug Discovery

Spyrakis

Sarkar

Kellogg

2021

Burger's Medicinal Chemistry and Drug Discovery

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Since its introduction about four decades ago, docking and scoring are now the very heart of structure‐based drug design. The past 10–20 years have seen a plethora of docking and scoring tools successfully integrated into drug discovery pipelines. Interestingly, while artificial intelligence is now receiving significant attention in the computational modeling arena, docking and scoring have long utilized these techniques. This comprehensive summary highlights some of the most significant achievements of docking and scoring, reviews the current status, provides descriptions of many of the tools available, comments on some of the outstanding challenges facing the paradigm, and offers perspectives and advice on best practices for users. While significant development is still needed in docking of flexible molecules and accurate Gibb's free energy predictions, docking and scoring are very useful when handled by experienced practitioners, but less so if treated as a “black box.” Lastly, we present a hypothetical case so beginners may appreciate the nuances of setting up a docking study. Focus in docking is now shifting toward parallel applications, i.e. protein–protein, protein–oligosaccharide, protein–DNA, or protein–RNA docking and polypharmacology. In summary, this article is intended to elucidate the nuances of the subject, while providing guidelines for practical implementation of effective workflows in drug discovery and structural biology.

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Blood–brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery

Abstract: Dual track screening of a small molecule library for drugs that have the dual properties of affinity for a neural cell drug receptor target, and affinity for a BBB CMT transporter target, can lead to a revolution in how small molecule drugs are identified in CNS drug discovery programs.

Cited by 116 publications

References 66 publications

Establishment and Dysfunction of the Blood-Brain Barrier

Establishment and Dysfunction of the Blood-Brain Barrier

Urban Policies and Mobility Trends in Italian Smart Cities

Docking, Scoring, and Virtual Screening in Drug Discovery

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