Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

Vu, Hoan; Pedro, Liliana; Mak, Tin; McCormick, B. P.; Rowley, Jessica; Liu, Miaomiao; Capua, Angela Di; Williams-Noonan, Billy J; Pham, Ngoc Bich; Pouwer, Rebecca H.; Nguyen, Bao; Andrews, Katherine Thea; Skinner‐Adams, Tina S.; Kim, Jessica; Hól, Wim G. J.; Hui, Raymond; Crowther, Gregory J.; Voorhis, Wesley C. Van; Quinn, Ronald J.

doi:10.1021/acsinfecdis.7b00197

Cited by 59 publications

(49 citation statements)

References 71 publications

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“…121 Adoption of this kind of biochemical target assessment in the eld of natural products can be seen in the recent extension of ligandability methodology to "native mass spectroscopy" experiments from the research group of R. J. Quinn. 122 An additional body of literature assessing which classes of both biochemical targets and chemical scaffolds have been most and least successful for HTS development has also recently emerged. 121,[123][124][125] These "target-class" assessments highlight potential limitations of a target or scaffold; but may not predict the behavior of either a novel target or a wellannotated target in a novel assay system.…”

Section: Target Selectionmentioning

confidence: 99%

Creating and screening natural product libraries

et al. 2020

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Section: Target Selectionmentioning

confidence: 99%

Creating and screening natural product libraries

et al. 2020

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“…A library of 643 natural products with fragment-like physicochemical properties was assembled as a screening library [30].…”

Section: Design Of Low Mw Librarymentioning

confidence: 99%

“…The malaria proteome has been examined by a fragmentbased approach using native mass spectrometry to detect protein-ligand interactions that exploit proteins produced by structural genomics efforts [30]. Using this assay, a fragment-sized library consisting of 643 natural products with molecular weight <250 were screened against 62 potential protein targets for malaria.…”

Section: P Falciparummentioning

confidence: 99%

“…Native mass spectrometry has been used with a natural product fragment library to examine potential drug targets from the malaria proteome. The use of low MW natural products as fragments in native mass spectrometry may represent the largest single dataset disclosed for a fragment-based drug screening campaign with 62 targets [30]. The library contained of only 643 unique low MW natural products [30].…”

Section: Expert Opinionmentioning

confidence: 99%

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Fragment-based screening with natural products for novel anti-parasitic disease drug discovery

Liu

Quinn

2019

Expert Opinion on Drug Discovery

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Introduction: Fragment-based drug discovery can identify relatively simple compounds with low binding affinity due to fewer binding interactions with protein targets. FBDD reduces the library size and provides simpler starting points for subsequent chemical optimization of initial hits. A much greater proportion of chemical space can be sampled in fragment-based screening compared to larger molecules with typical molecular weights (MWs) of 250-500 g mol −1 used in high-throughput screening (HTS) libraries. Areas covered: The authors cover the role of natural products in fragment-based drug discovery against parasitic disease targets. They review the approaches to develop fragment-based libraries either using natural products or natural product-like compounds. The authors present approaches to fragment-based drug discovery against parasitic diseases and compare these libraries with the 3D attributes of natural products. Expert opinion: To effectively use the three-dimensional properties and the chemical diversity of natural products in fragment-based drug discovery against parasitic diseases, there needs to be a mindshift. Library design, in the medicinal chemistry area, has acknowledged that escaping flat-land is very important to increase the chances of clinical success. Attempts to increase sp 3 richness in fragment libraries are acknowledged. Sufficient low molecular weight natural products are known to create true natural product fragment libraries.

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“…A recent study described the use of fragment-sized NPs for target identification and hits discovery against Plasmodium falciparum (Vu et al, 2018). The group from SGC Toronto elegantly reported a strategy that involved screening of an in-house library containing 643 NPs (complying with, at least, five of the established criteria for fragment-like compounds (MW ≤ 250 Da, ALogP < 4, HBD ≤ 4, HBA ≤ 5, RB ≤ 6, %PSA < 45) against 62 proteins using a native mass spectrometry (MS) approach that allowed detection of protein-ligand interactions.…”

Section: A) Fragment-sized Natural Productsmentioning

confidence: 99%

Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Silva

Emery

2018

Braz. J. Pharm. Sci.

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Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp 3-hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity. To date, several approaches have been implemented for mapping and navigating into the chemical space of NPs to explore the different aspects of chemical space. The approaches providing novel opportunities to synthesize NP-inspired compound libraries involve NP-based fragments and ring distortion strategies. These methodologies allow access to areas of chemical space that are less explored, and consequently help to overcome the limitations in the use of NPs in drug discovery, such as lack of accessibility and synthetic intractability. In this review, we describe how NPs have recently been used as a platform for the development of diverse compounds with high structural and stereochemical complexity. In addition, we show developed strategies aiming to reengineer NPs toward the expansion of NP-based chemical space by fragment-based approaches and chemical degradation to yield novel compounds to enable drug discovery.

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Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

Cited by 59 publications

References 71 publications

Creating and screening natural product libraries

Creating and screening natural product libraries

Fragment-based screening with natural products for novel anti-parasitic disease drug discovery

Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

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