Screening of Heteroaromatic Scaffolds against Cystathionine Beta-Synthase Enables Identification of Substituted Pyrazolo[3,4-c]Pyridines as Potent and Selective Orthosteric Inhibitors

Cystathionine β-synthase (CBS) is a key enzyme in the production of the signaling molecule hydrogen sulfide, deregulation of which is known to contribute to a range of serious pathological states. Involvement of hydrogen sulfide in pathways of paramount importance for cellular homeostasis renders CBS a promising drug target. An in-house focused library of heteroaromatic compounds was screened for CBS modulators by the methylene blue assay and a pyrazolopyridine derivative with a promising CBS inhibitory potential was discovered. The compound activity was readily comparable to the most potent CBS inhibitor currently known, aminoacetic acid, while a promising specificity over the related cystathionine γ-lyase was identified. To rule out any possibility that the inhibitor may bind the enzyme regulatory domain due to its high structural similarity with cofactor s-adenosylmethionine, differential scanning fluorimetry was employed. A sub-scaffold search guided follow-up screening of related compounds, providing preliminary structure-activity relationships with respect to requisites for efficient CBS inhibition by this group of heterocycles. Subsequently, a hypothesis regarding the exact binding mode of the inhibitor was devised on the basis of the available structure-activity relationships (SAR) and a deep neural networks analysis and further supported by induced-fit docking calculations.

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Structure activity relationships and the binding mode of quinolinone-pyrimidine hybrids as reversal agents of multidrug resistance mediated by P-gp

Scientific Reports ◽

10.1038/s41598-021-96226-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jerónimo Laiolo ◽

Priscila Ailin Lanza ◽

Oscar Parravicini ◽

Cecilia Barbieri ◽

Daniel Insuasty ◽

...

Keyword(s):

Multidrug Resistance ◽

Molecular Complexes ◽

Binding Mode ◽

Reversal Agents ◽

Structure Activity Relationships ◽

Structure Activity ◽

Doxorubicin Toxicity ◽

Key Residues ◽

Nanomolar Range ◽

Experimental Structure

AbstractP-gp-associated multidrug resistance is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure–activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone to the moiety bearing the pyrimidine favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

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Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

10.21203/rs.3.rs-451061/v1 ◽

2021 ◽

Author(s):

Jerónimo Laiolo ◽

Priscila Ailin Lanza ◽

Oscar Parravicini ◽

Cecilia Barbieri ◽

Daniel Insuasty ◽

...

Keyword(s):

Multidrug Resistance ◽

Molecular Complexes ◽

Binding Mode ◽

Reversal Agents ◽

Structure Activity Relationships ◽

Structure Activity ◽

Doxorubicin Toxicity ◽

Key Residues ◽

Nanomolar Range ◽

Experimental Structure

Abstract P-gp-associated multidrug resistance (MDR) is a major impediment to the success of chemotherapy. With the aim of finding non-toxic and effective P-gp inhibitors, we investigated a panel of quinolin-2-one-pyrimidine hybrids. Among the active compounds, two of them significantly increased intracellular doxorubicin and rhodamine 123 accumulation by inhibiting the efflux mediated by P-gp and restored doxorubicin toxicity at nanomolar range. Structure-activity relationships showed that the number of methoxy groups, an optimal length of the molecule in its extended conformation, and at least one flexible methylene group bridging the quinolinone moiety favored the inhibitory potency of P-gp. The best compounds showed a similar binding pattern and interactions to those of doxorubicin and tariquidar, as revealed by MD and hybrid QM/MM simulations performed with the recent experimental structure of P-gp co-crystallized with paclitaxel. Analysis of the molecular interactions stabilizing the different molecular complexes determined by MD and QTAIM showed that binding to key residues from TMH 4–7 and 12 is required for inhibition.

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Characterization of platinum(II) complexes exhibiting inhibitory activity against the 20S proteasome

Royal Society Open Science ◽

10.1098/rsos.200545 ◽

2020 ◽

Vol 7 (8) ◽

pp. 200545

Author(s):

Tatsuto Kiwada ◽

Hiromu Katakasu ◽

Serina Okumura ◽

Akira Odani

Keyword(s):

Inhibitory Activity ◽

Chemical Structure ◽

Competitive Inhibition ◽

Proteasome Inhibitors ◽

Platinum Complex ◽

Platinum Complexes ◽

Binding Mode ◽

Structure Activity Relationships ◽

Structure Activity

Proteasome inhibitors are useful for biochemical research and clinical treatment. In our previous study, we reported that the 4N-coordinated platinum complexes with anthracenyl ring and heterocycle exhibited proteasome-inhibitory activity. In the present study, the structure–activity relationships and characterization of these complexes were determined for the elucidation of the role of aromatic ligands. Lineweaver–Burk analysis revealed that the chemical structure of heterocycles affects the binding mode of platinum complexes. Platinum complexes with anthracenyl ring and pyridine showed competitive inhibition, although platinum complexes with anthracenyl ring and phenanthroline showed non-competitive inhibition. The structure–activity relationships demonstrated that anthracenyl moiety plays a crucial role in proteasome-inhibitory activity. The platinum complexes with naphthyl or phenyl rings exhibited lower inhibitory activities than the platinum complex with anthracenyl ring. The reactivity with N-acetylcysteine varied according to the chemical structure of complexes.

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From Molecular Docking to 3D-Quantitative Structure-Activity Relationships (3D-QSAR): Insights into the Binding Mode of 5-Lipoxygenase Inhibitors

Molecular Informatics ◽

10.1002/minf.201100101 ◽

2012 ◽

Vol 31 (2) ◽

pp. 123-134 ◽

Cited By ~ 10

Author(s):

Gokcen Eren ◽

Antonio Macchiarulo ◽

Erden Banoglu

Keyword(s):

Molecular Docking ◽

3D Qsar ◽

Binding Mode ◽

Quantitative Structure ◽

Lipoxygenase Inhibitors ◽

Structure Activity Relationships ◽

Structure Activity ◽

Quantitative Structure Activity Relationships

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The structure–activity relationships of A-ring-substituted aromathecin topoisomerase I inhibitors strongly support a camptothecin-like binding mode

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2010.06.040 ◽

2010 ◽

Vol 18 (15) ◽

pp. 5535-5552 ◽

Cited By ~ 12

Author(s):

Maris A. Cinelli ◽

Andrew E. Morrell ◽

Thomas S. Dexheimer ◽

Keli Agama ◽

Surbhi Agrawal ◽

...

Keyword(s):

Topoisomerase I ◽

Binding Mode ◽

Structure Activity Relationships ◽

Topoisomerase I Inhibitors ◽

Structure Activity

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Structure-Activity Relationships and Binding Mode in the Human Acetylcholinesterase Active Site of Pseudo-Irreversible Inhibitors Related to Xanthostigmine

ChemMedChem ◽

10.1002/cmdc.200800396 ◽

2009 ◽

Vol 4 (4) ◽

pp. 670-679 ◽

Cited By ~ 15

Author(s):

Stefano Rizzo ◽

Andrea Cavalli ◽

Luisa Ceccarini ◽

Manuela Bartolini ◽

Federica Belluti ◽

...

Keyword(s):

Active Site ◽

Binding Mode ◽

Structure Activity Relationships ◽

Irreversible Inhibitors ◽

Structure Activity

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Identification of the first surrogate agonists for the G protein-coupled receptor GPR132

RSC Advances ◽

10.1039/c5ra04804d ◽

2015 ◽

Vol 5 (60) ◽

pp. 48551-48557 ◽

Cited By ~ 5

Author(s):

Mohamed A. Shehata ◽

Hanna Belcik Christensen ◽

Vignir Isberg ◽

Daniel Sejer Pedersen ◽

Andreas Bender ◽

...

Keyword(s):

G Protein ◽

Binding Mode ◽

Orphan Receptor ◽

G Protein Coupled Receptor ◽

Structure Activity Relationships ◽

Structure Activity ◽

G Protein Coupled

We report the first pharmacological tool agonist for in vitro characterization of the orphan receptor GPR132, preliminary structure–activity relationships based on 32 analogs and a suggested binding mode from docking.

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