Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics

Merk, Daniel; Grisoni, Francesca; Friedrich, Lukas; Gelžinytė, Elena; Schneider, Gisbert

doi:10.1021/acs.jmedchem.8b00494

Cited by 44 publications

(53 citation statements)

References 26 publications

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“…In subsequent work, the same group has successfully developed tetrahydroindoles as natural product inspired RXR ligands. [63] Thec ompound 22 (Figure 19) activated all three RXR subtypes with low micromolar potencya nd inherited the high trans-activation efficacyo fi ts design template valerenic acid on RXRb.R ecently,t he design concept has successfully been applied to generating novel anticancer peptides. [64]…”

Section: Retinoid Xand Peroxisome Proliferator-activated Receptor Agomentioning

confidence: 99%

Automated De Novo Drug Design: Are We Nearly There Yet?

2019

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Medicinal chemistry and, in particular, drug design have often been perceived as more of an art than a science. The many unknowns of human disease and the sheer complexity of chemical space render decision making in medicinal chemistry exceptionally demanding. Computational models can assist the medicinal chemist in this endeavour. Provided here is an overview of recent examples of automated de novo molecular design, a discussion of the concepts and computational approaches involved, and the daring prediction of some of the possibilities and limitations of drug design using machine intelligence.

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Section: Retinoid Xand Peroxisome Proliferator-activated Receptor Agomentioning

confidence: 99%

Automated De Novo Drug Design: Are We Nearly There Yet?

2019

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“…Molecule 58 was the most potent analogue activating RXRs with low micromolar potency and upregulating ABCA1 and Apo E expression. This study indicates that natural products are excellent templates for designing synthetic drugs against the RXRs …”

Section: Rxr Agonistsmentioning

confidence: 71%

“…Preliminary in vitro characterization indicated the RXRα agonistic activity of 54 to 56 at a concentration of 30 μM. The compounds were also able to induce ABCA1 and ApoE expression . Then, the software Design of Genuine Structures was used to generate structures based in 53 , and compounds 54 to 56 .…”

Section: Rxr Agonistsmentioning

confidence: 99%

A review of the molecular design and biological activities of RXR agonists

Almeida

Conda‐Sheridan

2019

Medicinal Research Reviews

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An attractive approach to combat disease is to target theregulation of cell function. At the heart of this task are nuclear receptors (NRs); which control functions such as gene transcription. Arguably, the key player in this regulatory machinery is the retinoid X receptor (RXR). This NR associates with a third of the NRs found in humans. Scientists have hypothesized that controlling the activity of RXR is an attractive approach to control cellular functions that modulate diseases such as cancer, diabetes, Alzheimer's disease and Parkinson's disease. In this review, we will describe the key features of the RXR, present a historic perspective of the first RXR agonists, and discuss various templates that have been reported to activate RXR with a focus on their molecular structure, biological activity, and limitations. Finally, we will present an outlook of the field and future directions and considerations to synthesize or modulate RXR agonists to make these compounds a clinical reality.

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“…CATS2 descriptors are based on the occurrence of pharmacophore feature pairs (lipophilic, aromatic, hydrogen‐bond acceptor, and hydrogen‐bond donor atoms) at topological distances up to ten bonds and are specifically developed for scaffold hopping . In previous studies, CATS2 enabled the identification of novel modulators of another nuclear receptor (retinoid X receptor) Similarity of 3D pharmacophore feature distributions (LIQUID) based on 17 selected FXR agonists as templates.…”

Section: Resultsmentioning

confidence: 99%

“…[13] In previous studies, CATS2enabled the identification of novel modulators of anothernuclear receptor (retinoid Xr eceptor). [14,15] 2) Similarity of 3D pharmacophore feature distributions (LIQUID) [16] based on 17 selected FXR agonists as templates.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Molecular Frameworks of Farnesoid X Receptor Modulators by Ensemble Machine Learning

et al. 2018

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The bile acid activated transcription factor farnesoid X receptor (FXR) has revealed therapeutic potential as a molecular drug target for the treatment of hepatic and metabolic disorders. Despite strong efforts in FXR ligand development, the structural diversity among the known FXR modulators is limited. Only four molecular frameworks account for more than 50 % of the FXR modulators annotated in ChEMBL. Here, we leverage machine learning methods to expand the chemical space of FXR‐targeting small molecules by employing an ensemble of three complementary machine learning approaches. A counter‐propagation artificial neural network, a k‐nearest neighbor learner, and a three‐dimensional pharmacophore descriptor were combined to retrieve novel FXR ligands from a collection of more than 3 million compounds. The ensemble machine learning model identified six new FXR modulators among ten top‐ranked candidates. These active hits comprise both FXR activators and antagonists with micromolar potencies. With four novel FXR ligand scaffolds, these computationally identified bioactive compounds appreciably expand the chemical space of known FXR modulators and may serve as starting points for hit‐to‐lead expansion.

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Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics

Cited by 44 publications

References 26 publications

Automated De Novo Drug Design: Are We Nearly There Yet?

Automated De Novo Drug Design: Are We Nearly There Yet?

A review of the molecular design and biological activities of RXR agonists

Discovery of Novel Molecular Frameworks of Farnesoid X Receptor Modulators by Ensemble Machine Learning

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