Abstract
The discovery of novel ligand chemotypes allows to explore uncharted regions in chemical space, thereby potentially improving synthetic accessibility, potency, and the drug-likeness of molecules. Here, we demonstrate the scaffold-hopping ability of the new Weighted Holistic Atom Localization and Entity Shape (WHALES) molecular descriptors compared to seven state-of-the-art molecular representations on 30,000 compounds and 182 biological targets. In a prospective application, we apply WHALES to the discovery of novel retinoid X receptor (RXR) modulators. WHALES descriptors identified four agonists with innovative molecular scaffolds, populating uncharted regions of the chemical space. One of the agonists, possessing a rare non-acidic chemotype, revealed high selectivity on 12 nuclear receptors and comparable efficacy as bexarotene on induction of ATP-binding cassette transporter A1, angiopoietin like protein 4 and apolipoprotein E. The outcome of this research supports WHALES as an innovative tool to explore novel regions of the chemical space and to detect novel bioactive chemotypes by straightforward similarity searching.
Highlights
We have developed a novel molecular representation, the WHALES (Weighted Holistic Atom Localization and Entity Shape) descriptors[23], which were originally designed to transfer relevant structural and pharmacophore information encoded in known bioactive natural products (NP) to synthetically more accessible isofunctional compounds through similarity-driven approaches
The WHALES calculation procedure is performed in five steps:
Blue dots represent the cases where the SDA% of WHALES-GM in the top 1% of the list was more than 3% larger than WHALES-density-functional-based tight-binding (DFTB)+
Summary
We have developed a novel molecular representation, the WHALES (Weighted Holistic Atom Localization and Entity Shape) descriptors[23], which were originally designed to transfer relevant structural and pharmacophore information encoded in known bioactive natural products (NP) to synthetically more accessible isofunctional compounds through similarity-driven approaches. In the proof-of-concept study[23], WHALES identified seven natural-product-inspired synthetic compounds that modulate the cannabinoid receptor, with innovative scaffolds compared to actives annotated in ChEMBL24. We performed a systematic retrospective virtual screening, to (i) determine the scaffold-hopping ability of WHALES with synthetic compounds as queries, and (ii) compare the performance of WHALES with seven state-of-the-art molecular descriptors. In this context, WHALES confirmed to possess a desirable scaffold-hopping ability, outperforming the state-of-the-art methods in 89% of the tested biological receptors. The scaffold-hopping ability of WHALES was confirmed by a prospective, experimental application of WHALES in www.nature.com/scientificreports/. Finding synthetic modulators of the retinoid X receptor (RXR), through the identification of four novel agonists, including a new non-acidic RXR agonist chemotype
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