Identification of 5-nitroindazole as a multitargeted inhibitor for CDK and transferase kinase in lung cancer: a multisampling algorithm-based structural study

Ahmad, Shaban; Raza, Khalid

doi:10.1007/s11030-023-10648-0

Cited by 34 publications

(5 citation statements)

References 41 publications

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“…MD simulation was performed using the Desmond v3 . 6 package from Schrodinger, where we illustrated high density at the centre of a 10 × 10 × 10 Å orthorhombic box with the periodic frontier condition in NPT ensemble class in a buffer medium 62 , 63 . This module helps determine the RMSD value, Protein–Ligand torsion, protein–ligand interaction, validation, and optimization.…”

Section: Methodsmentioning

confidence: 99%

In-silico and in-vitro study reveals ziprasidone as a potential aromatase inhibitor against breast carcinoma

Sahu,

Ahmad,

Imtiyaz

et al. 2023

Sci Rep

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Aromatase enzyme plays a fundamental role in the development of estrogen receptors, and due to this functionality, the enzyme has gained significant attention as a therapeutic for reproductive disorders and cancer diseases. The currently employed aromatase inhibitors have severe side effects whereas our novel aromatase inhibitor is more selective and less toxic, therefore has greater potential to be developed as a drug. The research framework of this study is to identify a potent inhibitor for the aromatase target by profiling molecular descriptors of the ligand and to find a functional pocket in the target by docking and MD simulations. For assessing cellular and metabolic activities as indicators of cell viability and cytotoxicity, in-vitro studies were performed by using the colorimetric MTT assay. Aromatase activities were determined by a fluorometric method. Cell morphology was assessed by phase-contrast light microscopy. Flow cytometry and Annexin V-FITC/PI staining assay determined cell cycle distribution and apoptosis. This study reports that CHEMBL708 (Ziprasidone) is the most promising compound that showed excellent aromatase inhibitory activity. By using better drug design methods and experimental studies, our study identified a novel compound that could be effective as a high-potential drug candidate against aromatase enzyme. We conclude that the compound ziprasidone effectively blocks the cell cycle at the G1-S phase and induces cancer cell death. Further, in-vivo studies are vital for developing ziprasidone as an anticancer agent. Lastly, our research outcomes based on the results of the in-silico experiments may pave the way for identifying effective drug candidates for therapeutic use in breast cancer.

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Section: Methodsmentioning

confidence: 99%

In-silico and in-vitro study reveals ziprasidone as a potential aromatase inhibitor against breast carcinoma

Sahu,

Ahmad,

Imtiyaz

et al. 2023

Sci Rep

Self Cite

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“…The molecular docking-based screening was performed using the Virtual Screening Workflow (VSW) tool, and in the input tab, we browsed the prepared library of the ligand. In the filtering tab, we used the QikProp to generate the compounds’ pharmacokinetic properties and the properties were passed to Lipinski’s rules to filter further [ 45 , 46 , 47 , 48 ]. We skipped the preparation step as our ligand was already prepared, and in the receptor tab, we browsed each receptor grid.…”

Section: Methodsmentioning

confidence: 99%

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

Hakami,

Hazazi,

Albloui

et al. 2024

IJMS

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Lung cancer is a pervasive and challenging disease with limited treatment options, with global health challenges often present with complex molecular profiles necessitating the exploration of innovative therapeutic strategies. Single-target drugs have shown limited success due to the heterogeneity of this disease. Multitargeted drug designing is imperative to combat this complexity by simultaneously targeting multiple target proteins and pathways, which can enhance treatment efficacy and overcome resistance by addressing the dynamic nature of the disease and stopping tumour growth and spread. In this study, we performed the molecular docking studies of Drug Bank compounds with a multitargeted approach against crucial proteins of lung cancer such as heat shock protein 5 (BIP/GRP78) ATPase, myosin 9B RhoGAP, EYA2 phosphatase inhibitor, RSK4 N-terminal kinase, and collapsin response mediator protein-1 (CRMP-1) using HTVS, SP with XP algorithms, and poses were filtered using MM\GBSA which identified [3-(1-Benzyl-3-Carbamoylmethyl-2-Methyl-1h-Indol-5-Yloxy)-Propyl-]-Phosphonic Acid (3-1-BenCarMethIn YlPro-Phosphonic Acid) (DB02504) as multitargeted drug candidate with docking and MM\GBSA score ranges from −5.83 to −10.66 and −7.56 to −50.14 Kcal/mol, respectively. Further, the pharmacokinetic and QM-based DFT studies have shown complete acceptance results, and interaction fingerprinting reveals that ILE, GLY, VAL, TYR, LEU, and GLN were among the most interacting residues. The 100 ns MD simulation in the SPC water model with NPT ensemble showed stable performance with deviation and fluctuations <2 Å with huge interactions, making it a promising multitargeted drug candidate; however, experimental studies are needed before use.

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“…To conduct the molecular dynamics simulation, 10 Å×10 Å×10 Å orthorhombic simulation boxes were generated, and isotonic saline solutions were emulated along with additional Na + or Clions the neutralize the net charge of the system. NPT ensemble was utilized at 300 K temperature and 1.02325 base pressure, and snapshots were taken every 100 picoseconds to obtain 1000 frame trajectories [72].…”

Section: In Silico Molecular Docking Molecular Dynamics and Admet Stu...mentioning

confidence: 99%

An in vivo and in silico evaluation of the hepatoprotective potential of Gynura procumbens: A promising agent for combating hepatotoxicity

Tithi,

Tahsin,

Anjum

et al. 2023

PLoS ONE

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Introduction The liver, the most important metabolic organ of the body, performs a wide variety of vital functions. Hepatic cell injury occurs by the activation of reactive oxygen species (ROS) that are generated by carbon tetrachloride (CCl4), xenobiotics, and other toxic substances through cytochrome P450-dependent steps resulting from the covalent bond formation with lipoproteins and nucleic acids. Observing the urgent state of hepatotoxic patients worldwide, different medicinal plants and their properties can be explored to combat such free radical damage to the liver. In vivo and in silico studies were designed and conducted to evaluate the antioxidant and hepatoprotective properties of Gynura procumbens in rats. Materials and methods Gynura procumbens leaves were collected and extracted using 70% ethanol. The required chemicals CCl4, standard drug (silymarin), and blood serum analysis kits were stocked. The in vivo tests were performed in 140 healthy Wister albino rats of either sex under well-controlled parameters divided into 14 groups, strictly maintaining Institutional Animal Ethics Committee (IEAC) protocols. For the histopathology study, 10% buffered neutral formalin was used for organ preservation. Later the specimens were studied under a fluorescence microscope. In silico molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were performed, and the results were analyzed statistically. Results and discussion Gynura procumbens partially negate the deleterious effect of carbon tetrachloride on normal weight gain in rats. The elevated level of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), creatinine, LDH, total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG), malondialdehyde (MDA), deoxyribonucleic acid (DNA) fragmentation ranges, gamma-glutamyl transferase (γ-GT) in CCl4 treated groups were decreased by both standard drug silymarin and G. procumbens leaf extract. We have found significant & highly significant changes statistically for different doses, here p<0.05 & p<0.01, respectively. On the other hand, G. procumbens and silymarin displayed Statistically significant (p<0.05) and high significant(p<0.01) increased levels of HDL, CAT SOD (here p<0.05 & p<0.01 for different doses) when the treatment groups were compared with the disease control group. Because the therapeutic activity imparted by plants and drugs accelerates the movement of the disturbed pathophysiological state toward the healthy state. In the molecular docking analysis, G. procumbens phytoconstituents performed poorly against transforming growth factor-beta 1 (TGF-β1) compared to the control drug silymarin. In contrast, 26 phytoconstituents scored better than the control bezafibrate against peroxisome proliferator-activated receptor alpha (PPAR-α). The top scoring compounds for both macromolecules were observed to form stable complexes in the molecular dynamics simulations. Flavonoids and phenolic compounds performed better than other constituents in providing hepatoprotective activity. It can, thus, be inferred that the extract of G. procumbens showed good hepatoprotective properties in rats.

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Identification of 5-nitroindazole as a multitargeted inhibitor for CDK and transferase kinase in lung cancer: a multisampling algorithm-based structural study

Cited by 34 publications

References 41 publications

In-silico and in-vitro study reveals ziprasidone as a potential aromatase inhibitor against breast carcinoma

In-silico and in-vitro study reveals ziprasidone as a potential aromatase inhibitor against breast carcinoma

Delineated 3-1-BenCarMethInYlPro-Phosphonic Acid’s Adroit Activity against Lung Cancer through Multitargeted Docking, MM\GBSA, QM-DFT and Multiscale Simulations

An in vivo and in silico evaluation of the hepatoprotective potential of Gynura procumbens: A promising agent for combating hepatotoxicity

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