SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

He, Shuwen; Dobbelaar, Peter H.; Guo, Liangqin; Ye, Zhixiong; Liu, Jian; Jian, Tianying; Truong, Quang; Shah, Shrenik K.; Du, Wu; Qi, Hongbo; Bakshi, Raman K.; Hong, Qingmei; Dellureficio, James; Sherer, Edward C.; Pasternak, Alexander; Feng, Zhe; Reibarkh, Mikhail; Lin, Melissa; Samuel, Koppara; Reddy, Vijay Bhasker G.; Mitelman, Stan; Tong, Sharon; Chicchi, Gary G.; Tsao, Kwei-Lan; Trusca, Dorina; Wu, Margaret; Shao, Qing; Trujillo, María E.; Fernandez, Guillermo; Nelson, Donald J.; Bunting, Patricia B.; Kerr, Janet S.; Fitzgerald, Patrick; Morissette, Pierre; Volksdorf, Sylvia; Eiermann, George J.; Li, Cai; Zhang, Bei B.; Howard, Andrew D.; Zhou, Yunping; Nargund, Ravi P.

doi:10.1016/j.bmcl.2016.02.022

Cited by 9 publications

(6 citation statements)

References 7 publications

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“…78 For each cluster, the compound responsible for the lower IC 50 value was selected for further induced-fit docking (IFD) simulations. In doing that, ligands corresponding to the following ID in ChEMBL were selected: CHEMBL271066 (IC 50 = 6.31 nM), 82 CHEMBL1257698 (IC 50 = 0.38 nM), 83 CHEMBL3775456 (IC 50 = 58.49 nM), 84 CHEMBL3422978 (IC 50 = 0.39 nM), 85 and CHEMBL2146867 (IC 50 = 0.76 nM) 86 (see Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Creanza

Delre

Ancona

et al. 2021

J. Chem. Inf. Model.

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Drug-induced blockade of the human ether-a-go-gorelated gene (hERG) channel is today considered the main cause of cardiotoxicity in postmarketing surveillance. Hence, several ligandbased approaches were developed in the last years and are currently employed in the early stages of a drug discovery process for in silico cardiac safety assessment of drug candidates. Herein, we present the first structure-based classifiers able to discern hERG binders from nonbinders. LASSO regularized support vector machines were applied to integrate docking scores and protein−ligand interaction fingerprints. A total of 396 models were trained and validated based on: (i) high-quality experimental bioactivity information returned by 8337 curated compounds extracted from ChEMBL (version 25) and (ii) structural predictor data. Molecular docking simulations were performed using GLIDE and GOLD software programs and four different hERG structural models, namely, the recently published structures obtained by cryoelectron microscopy (PDB codes: 5VA1 and 7CN1) and two published homology models selected for comparison. Interestingly, some classifiers return performances comparable to ligand-based models in terms of area under the ROC curve (AUC MAX = 0.86 ± 0.01) and negative predictive values (NPV MAX = 0.81 ± 0.01), thus putting forward the herein proposed computational workflow as a valuable tool for predicting hERG-related cardiotoxicity without the limitations of ligand-based models, typically affected by low interpretability and a limited applicability domain. From a methodological point of view, our study represents the first example of a successful integration of docking scores and protein−ligand interaction fingerprints (IFs) through a support vector machine (SVM) LASSO regularized strategy. Finally, the study highlights the importance of using hERG structural models accounting for ligand-induced fit effects and allowed us to select the best-performing protein conformation (made available in the Supporting Information, SI) to be employed for a reliable structure-based prediction of hERG-related cardiotoxicity.

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Section: Methodsmentioning

confidence: 99%

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Creanza

Delre

Ancona

et al. 2021

J. Chem. Inf. Model.

View full text Add to dashboard Cite

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“…SST 3 agonists inhibit insulin release from INS-1 cells ( Mergler et al, 2008 ). At the systemic level, highly selective SST 3 antagonists such as MK-1421 or MK-4256 facilitate glucose-stimulated insulin secretion from pancreatic β -cells and block glucose excursion in wild-type, but not SST 3 KO mice ( Pasternak et al, 2012 ; Shah et al, 2015 ; He et al, 2016 ). This suggests that SST 3 antagonism represents a new potential mechanism for treating type 2 diabetes mellitus.…”

Section: Somatostatin Receptormentioning

confidence: 99%

“…14 ; Table 6 ) ( Reubi et al, 2000a ). Great progress has been made in development of two structurally distinct classes of selective nonpeptide SST 3 antagonists based on tetrahydro- β -carboline and decahydroisoquinoline derivatives ( Poitout et al, 2001 ; Troxler et al, 2010 ; He et al, 2016 ). The decahydroisoquinoline derivative ACQ090 is a full neutral antagonist that blocks phosphorylation and internalization of SST 3 completely ( Fig.…”

Section: Somatostatin Receptormentioning

confidence: 99%

“…Tetrahydro- β -carboline derivatives such as MK-1421 or MK-4256 are highly selective for SST 3 . They were shown to facilitate glucose-stimulated insulin secretion from pancreatic β -cells and block glucose excursion in rodents in vivo ( Pasternak et al, 2012 ; Shah et al, 2015 ; He et al, 2016 ). MK-4256 has been evaluated as a potential candidate for treatment of type 2 diabetes mellitus ( Fig.…”

Section: Somatostatin Receptormentioning

confidence: 99%

“…MK-4256 has been evaluated as a potential candidate for treatment of type 2 diabetes mellitus ( Fig. 14 ; Table 6 ) ( He et al, 2012 , 2016 ; Shah et al, 2015 ). However, development was discontinued due to adverse cardiovascular effects related to human ether-a-go-go–related gene off-target side effects ( He et al, 2014 ).…”

Section: Somatostatin Receptormentioning

confidence: 99%

See 2 more Smart Citations

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

et al. 2018

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Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.

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Recent Advances on the Synthesis and Application of Tetrahydro‐β‐Carbolines

Du,

Semghouli,

Mei

et al. 2024

Adv Synth Catal

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Abstract. Tetrahydro‐β‐carbolines (THβCs) also known as tryptolines serve as important structural elements in natural products and pharmaceutical compounds, and they are also utilized in drug discovery. They display diverse bioactivities, including anticancer, antifungal, antiparasitic, anti‐ischemic, anti‐inflammatory, and other activities. Besides their pharmacological and biological significance, these structural motifs are also extensively used in the production of other bioactive compounds. This review is intended to summarize recent advancements in the chemistry of this compound class, including the synthesis and the applications as organic synthetic intermediates and bioactive molecules.

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SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

Cited by 9 publications

References 7 publications

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature

Recent Advances on the Synthesis and Application of Tetrahydro‐β‐Carbolines

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