Cross evaluation of different classes of alpha-adrenergic receptor antagonists to identify overlapping pharmacophoric requirements

Pandey, Neetesh; Yadav, Mukesh; Nayarisseri, Anuraj; Ojha, Meenakshi; Prajapati, Jyoti; Gupta, Saurabh

doi:10.1016/j.jopr.2012.11.036

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…5B). The quinazoline scaffold of non-protonated prazosin was docked close to TM5 to form a hydrogen bond between the 6,7-methoxy groups and SER188 11,12 , a hydrogen bond between the furan oxygen and SER83, and between the prazosin carboxamide and GLN177 side chain; van der Waals interactions with side chains of PHE86, VAL107, ILE178, SER192 11 , PHE289 13 , MET292 and PHE312 12,14 ; π-π interactions with PHE288 and PHE312 12 ; and a π-hydrogen bond interaction with the side chain carboxyl group and backbone peptide carboxamide of ASP106 12,15 . Thus, the proposed binding mode of non-protonated prazosin utilized interactions that were in accord with those described in previous literature.…”

Section: Resultsmentioning

confidence: 99%

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

Nakladal

Buikema

Romero

et al. 2019

Sci Rep

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SUL-compounds are protectants from cold-induced ischemia and mitochondrial dysfunction. We discovered that adding SUL-121 to renal grafts during warm machine reperfusion elicits a rapid improvement in perfusion parameters. Therefore, we investigate the molecular mechanisms of action in porcine intrarenal arteries (PIRA). Porcine kidneys were stored on ice overnight and perfusion parameters were recorded during treatment with SUL-compounds. Agonist-induced vasoconstriction was measured in isolated PIRA after pre-incubation with SUL-compounds. Receptor binding and calcium transients were assessed in α1-adrenoceptor (α1-AR) transgenic CHO cells. Molecular docking simulation was performed using Schrödinger software. Renal pressure during warm reperfusion was reduced by SUL-121 (−11.9 ± 2.50 mmHg) and its (R)-enantiomer SUL-150 (−13.2 ± 2.77 mmHg), but not by the (S)-enantiomer SUL-151 (−1.33 ± 1.26 mmHg). Additionally, SUL-150 improved renal flow (16.21 ± 1.71 mL/min to 21.94 ± 1.38 mL/min). SUL-121 and SUL-150 competitively inhibited PIRA contraction responses to phenylephrine, while other 6-chromanols were without effect. SUL-150 similarly inhibited phenylephrine-induced calcium influx and effectively displaced [7-Methoxy-3H]-prazosin in CHO cells. Docking simulation to the α1-AR revealed shared binding characteristics between prazosin and SUL-150. SUL-150 is a novel α1-AR antagonist with the potential to improve renal graft perfusion after hypothermic storage. In combination with previously reported protective effects, SUL-150 emerges as a novel protectant in organ transplantation.

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Section: Resultsmentioning

confidence: 99%

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

Nakladal

Buikema

Romero

et al. 2019

Sci Rep

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“…The free interface of admetSAR tool was used (http://lmmd.ecust. edu.cn:8000/) (Natchimuthu et al, 2016;Chandrakar et al, 2013;Pandey et al, 2013).The compounds which carried greater affinity score from established compounds and virtual screened compounds after docking were used to analyze the ADMET competency (Sinha et al, 2015;Sinha et al, 2014;Trishang et al, 2019;Vuree et al, 2013;Gudala et al, 2015).…”

Section: Admet Studiesmentioning

confidence: 99%

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

Sweta¹,

Khandelwal²,

Srinitha³

et al. 2019

Asian Pac J Cancer Prev

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According to the American Cancer Society (ACS), Acute Myeloid Leukemia (AML) is a group of hematological diseases, phenotypic and genetically heterogeneous, characterized by clonal expansion of myeloid with diminished capacity for differentiation. It is characterized by the fast growth of white blood cells, red blood cells, platelets, and it's a build-up in the bone marrow restricting the production of traditional blood cells. Once healthy bone marrow cells are replaced with the leukemic cells, it results in a decline in red blood cells, platelets, and healthy white blood cells. Mainly, symptoms that are seen in patients affected by AML are Weight loss, Fatigue, Fever, Night sweat, Loss of appetite, shortness of breath, natural bruising and bleeding, with lots of body

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“…X-ray crystal structure of the ERα in complex with 4-hydroxytamoxifen (OHT)(PDB Id: 3ERT [29] was selected for the present study by considering Resolution (1.9 Å), and R-Value Free (0.262) as speci c selection parameters from the Protein Data Bank [30][31][32][33][34][35][36][37][38]. Before proceeding to dock, the PDB structure was prepared using the Protein Preparation Wizard module(Schrodinger, Inc., LLC, New York, USA) by applying criteria like removal of water molecules, assigning bond orders, lling missing hydrogens, side chains & loops, capping termini, selenomethionine to methionine reconversion, optimization and energy minimization using the OPLS-2005 force eld with default settings [39][40][41][42][43][44][45][46][47][48][49][50].…”

Section: Target Selection and Protein Preparationmentioning

confidence: 99%

Structural insights into conformational stability of ESR1 and structure base screening of new potent inhibitor for the treatment of Breast Cancer

Chopra¹,

Panwar

Madhavi

et al. 2022

Preprint

Self Cite

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Estrogen receptor alpha (ERα), a nuclear receptor proteinencoded by the estrogen receptor1 (ESR1) gene,is an important biomarker in breast cancer diagnosis. Any dysregulation in its expression can actively implicate the development and progression of the disease. ERα is abnormally expressed in around 60% of the active cases, making it animportant therapeutic target. In this study, we report the application of computational approaches to identify suitable drug-like molecules, which share similar ligand binding dynamics with ERα. Structure-based virtual screening(SBVS), docking, and inhibitor dynamics are used to study the ligand binding and interaction profiling of the anticipatedligand molecule, at the active site of the 4-hydroxytamoxifen (OHT) protein (PDB Id: 3ERT). SBVS analysis follows HTVS, SP, and XP protocol in comparison to the ZINC and NCI, to retrieve 20 bestligandhits as effective inhibitors; All the compounds have shown significant interaction with active site residues (Leu346, Thr347, Asp351, Glu353, Trp383, Leu387, and Arg394) of the 4-hydroxytamoxifen. Moreover, the docking study was used to screen the top 5 compounds: ZINC13377936, NCI35753, ZINC35465238, ZINC14726791, and NCI663569. We also, employed molecular dynamics simulations to explore the binding dynamics present at the atomic level. Our MDS results have revealed the compounds (ZINC13377936 and NCI35753) with outstanding binding stability and lesser fluctuations. Both above hits possess a high potential as future therapeutic agents, acting by the mechanism of competitive inhibitionagainst the ERα protein in breast cancer.

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Cross evaluation of different classes of alpha-adrenergic receptor antagonists to identify overlapping pharmacophoric requirements

Cited by 3 publications

References 20 publications

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

Structural insights into conformational stability of ESR1 and structure base screening of new potent inhibitor for the treatment of Breast Cancer

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