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.
Highlights
I n 2015, malaria infected an estimated 212 million people globally, leading to 429 000 deaths, most of which were children aged 5 years and under in Africa.[1]
Native screening using high-resolution electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) is a label-free, fast, accurate method that permits the direct observation of Special Issue: Drug Discovery for Global Health
We previously reported the detection of protein−ligand interactions in complex natural product extracts.[18−20] We demonstrated that ESI-FT-ICR-MS can directly observe weak, noncovalent protein binding of fragment-sized natural products.[21]
Summary
I n 2015, malaria infected an estimated 212 million people globally, leading to 429 000 deaths, most of which were children aged 5 years and under in Africa.[1].
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