Semiemperical Investigation of the Postmenopausal Breast Cancer Treatment Potential of Xanthone Derivatives

Shahbazi, Sajad; Kuanar, Ananya

doi:10.4172/2329-6836.1000206

Cited by 8 publications

(5 citation statements)

References 29 publications

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“…QP log S and # metab are used to predict the aqueous solubility and number of likely metabolic reactions. 44 The results indicated that all three compounds were in the recommended ranges of QPPCaco and # metab. In the case of CIQP log S, all three compounds were not found to be in the acceptable range.…”

Section: Resultsmentioning

confidence: 92%

“…One of the factors to predict intestinal absorption or permeation is the Caco-2 cell permeability (QPPCaco), which is used as a model for the gut–blood barrier. QP log S and # metab are used to predict the aqueous solubility and number of likely metabolic reactions . The results indicated that all three compounds were in the recommended ranges of QPPCaco and # metab.…”

Section: Resultsmentioning

confidence: 99%

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High-Throughput Virtual Screening for a New Class of Antagonist Targeting LasR of Pseudomonas aeruginosa

et al. 2021

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Pseudomonas aeruginosa, an opportunistic human pathogen, causes fatal effects in patients with cystic fibrosis and immunocompromised individuals and leads to around 1000 deaths annually. The quorum sensing mechanism of P. aeruginosa plays a major role in promoting biofilm formation and expression of virulent genes. Hence, quorum sensing inhibition is a promising novel approach to treat these bacterial infections as these organisms show a wide range of antibiotic resistance. Among the interconnected quorum sensing network of P. aeruginosa, targeting the las system is of increased interest as its principal receptor protein LasR is the earliest activated gene. It is also shown to be involved in the regulation of other virulence-associated genes. In this study, we have applied high-throughput virtual screening, an in silico computational method to identify a new class of LasR inhibitors that could serve as potent antagonists to treat P. aeruginosa-associated infections. Three-tire structure-based virtual screening was performed on the Schrödinger small molecule database, which resulted in 12 top hit compounds with docking scores lesser than −11.0 kcal/mol. Three of these best-scored compounds CACPD2011a-0001928786 (C1), CACPD2011a-0001927437 (C2), and CACPD2011a-0000896051 (C3) were further analyzed. The binding free energies of these compounds in complex with the target protein LasR (3IX4) were evaluated, and the pharmacokinetic properties were determined. The stability of the docked complexes was assessed by running a molecular dynamics simulation for 100 ns. Molecular dynamics simulation analysis revealed that all three compounds were found to be in stable contact with the protein over the entire simulation period. The antagonistic effect of these compounds was validated using the LasR reporter gene assay in the presence of acyl homoserine lactone. Significant reduction in the β-galactosidase enzyme activity was achieved at 100 nM concentration for all three compounds pursued. Hence, the present study provides strong evidence that these three compounds could serve as quorum sensing inhibitors of P. aeruginosa LasR protein and can be a probable candidate to treat Pseudomonas-associated infections.

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Section: Resultsmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

High-Throughput Virtual Screening for a New Class of Antagonist Targeting LasR of Pseudomonas aeruginosa

et al. 2021

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“…MM‐GBSA is a popular method for predicting binding free energy. Scoring functions are used to predict the lowest energy poses, which determine the accuracy of docking results, and to predict the binding affinity of ligands toward the protein 24,25 . The top 10 docked ligands from the XP docking results were used to calculate MM‐GBSA free energy using the variable‐dielectric generalized born (VSGB) solvation model.…”

Section: Resultsmentioning

confidence: 99%

Unveiling the potential of marine compounds as quorum sensing inhibitors targeting Pseudomonas aeruginosa's LasI: A computational study using molecular docking and molecular dynamics

Singothu,

Begum,

Maddi

et al. 2023

J of Cellular Biochemistry

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Antimicrobial resistance (AMR) poses a significant threat to global public health, with multidrug‐resistant Pseudomonas aeruginosa being a leading cause of mortality, accounting for 18%–61% of deaths annually. The quorum sensing (QS) systems of P. aeruginosa, particularly the LasI‐LasR system, play a crucial role in promoting biofilm formation and expression of virulent genes, which contribute to the development of AMR. This study focuses on LasI, the mediator of biofilm formation for identifying its inhibitors from a marine compound database comprising of 32 000 compounds using molecular docking and molecular simulation techniques. The virtual screening and docking experiments demonstrated that the top 10 compounds exhibited favorable docking scores of <−7.19 kcal/mol compared to the reported inhibitor 3,5,7‐Trihydroxyflavone with a docking score of −3.098 kcal/mol. Additionally, molecular mechanics/Poisson‐Boltzmann generalized born surface area (MM‐GBSA) analyses were conducted to assess these compounds' suitability for further investigation. Out of 10 compounds, five compounds demonstrated high MM‐GBSA binding energy (<−35.33 kcal/mol) and were taken up for molecular dynamics simulations to evaluate the stability of the protein‐ligand complex over a 100 ns period. Based on root mean square deviation, root mean square fluctuation, radius of gyration, and hydrogen bond interactions analysis, three marine compounds, namely MC‐2 (CMNPD13419) and MC‐3 (CMNPD1068), exhibited consistent stability throughout the simulation. Therefore, these compounds show potential as promising LasI inhibitors and warrant further validation through in vitro and in vivo experiments. By exploring the inhibitory effects of these marine compounds on P. aeruginosa's QS system, this research aims to contribute to the development of novel strategies to combat AMR.

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“…Log S, #metab and QPPCaco-2 are the parameters for prediction of aqueous solubility levels, the number of likely metabolic reactions and permeability of the gut–blood barrier (nm/s), respectively. 43 Qikprop employs a complex set of parameters for the prediction of bioavailability, including RO3, human oral absorption percentage, qualitative human oral absorption and the conformation-independent aqueous solubility (CIlog S), based on the similarity of compounds with their close analogs, which were practically tested. If the similarity of a designed compound and a respective known analog is < 0.9, the Qikprop prediction is used for logS and logP (permeability prediction).…”

Section: Resultsmentioning

confidence: 99%

“…P pred is predicted property, S is the similarity, and P exp and P QP are the respective experimental and QikProp predictions for the most similar molecule within the training set. logP is predicted based on the physiochemical properties such as size, flexibility depending on the NRB, 43 overall lipophilicity, shape and the capacity to make hydrogen bonds.…”

Section: Resultsmentioning

confidence: 99%

Impact of novel N-aryl piperamide NO donors on NF-κB translocation in neuroinflammation: rational drug-designing synthesis and biological evaluation

et al. 2017

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NO donor drugs showed a significant therapeutic effect in the treatment of many diseases, such as arteriopathies, various acute and chronic inflammatory conditions, and several degenerative diseases. NO-releasing anti-inflammatory drugs are the prototypes of a novel class of compounds, combining the pharmacological activities of anti-inflammatory and anti-nociceptive of drugs with those of NO, thus possessing potential therapeutic applications in a great variety of diseases. In this study, we designed and predicted biological activity by targeting cyclooxygenase type 2 (COX-2) and NFkB subunits and pharmacological profiling along with toxicity predictions of various N-aryl piperamides linked via an ester bond to a spacer that is bound to a NO-releasing moiety (-ONO2). The result of absorption, distribution, metabolism and excretion and Docking studies indicated that among 51 designed molecules PA-3 0 K showed the best binding potential in both the substrate and inhibitory binding pocket of the COX-2 enzyme with affinity values of -9.33 and -5.12 for PDB ID 1CVU and 3LN1, respectively, thereby having the potential to be developed as a therapeutic agent. The results of cell viabilities indicated that PA-3 0 k possesses the best cell viability property with respect to its dose (17.33 ng/ml), with 67.76% and 67.93% viable cells for CHME3 and SVG cell lines, respectively.

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Semiemperical Investigation of the Postmenopausal Breast Cancer Treatment Potential of Xanthone Derivatives

Cited by 8 publications

References 29 publications

High-Throughput Virtual Screening for a New Class of Antagonist Targeting LasR of Pseudomonas aeruginosa

High-Throughput Virtual Screening for a New Class of Antagonist Targeting LasR of Pseudomonas aeruginosa

Unveiling the potential of marine compounds as quorum sensing inhibitors targeting Pseudomonas aeruginosa's LasI: A computational study using molecular docking and molecular dynamics

Impact of novel N-aryl piperamide NO donors on NF-κB translocation in neuroinflammation: rational drug-designing synthesis and biological evaluation

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