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

Abstract

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

Creating and screening natural product libraries

“…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.…”

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

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

“…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.…”

“…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].…”

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

“…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.…”