Synthesis, in vitro and structural aspects of cap substituted Suberoylanilide hydroxamic acid analogs as potential inducers of apoptosis in Glioblastoma cancer cells via HDAC /microRNA regulation

Ramaiah, M. Janaki; Ramalingam, Prasanna Srinivasan; Mathavan, Sivagami; Yamajala, Rajesh B. R. D.; Moparthi, Nageswara Rao; Kurappalli, Rohil Kumar; Reddy, M. Rajasekhar

doi:10.1016/j.cbi.2022.109876

Cited by 16 publications

(6 citation statements)

References 46 publications

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“…Initially, we retrieved the structural and molecular descriptors of nearly 1093 bioflavonoids with known biological activity, from PubChem and ChemFaces. Evaluation of drug-likeness and absorption and the distribution, metabolism, and excretion (ADME) properties of compounds plays a key role in the drug-discovery and development processes, by addressing safety and efficacy [ 31 , 32 ]. A total of 925 (duplicates removed) flavonoids were screened for their drug-likeness and ADME properties, using the SwissADME web server, which resulted in 514 flavonoids.…”

Section: Discussionmentioning

confidence: 99%

“…The binding energies and the inhibitory constant (Ki) determines the binding affinity of a ligand molecule toward the protein [ 31 ]. The steered molecular dynamics predict the time taken to dissociate the ligand from the protein by providing an external pulling force, and measure the binding affinity of the protein–ligand complex [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Lipinski’s rule, the rule of five (RO5), is widely used to predict the small molecules which are biologically active and orally bioavailable [ 30 ]. The RO5 states that the drug-likeness properties are that the molecular mass should be less than 500 Dalton, the hydrogen-bond donors should be fewer than 5, hydrogen-bond acceptors should be fewer than 10, and the partition coefficient log P or lipophilicity should be less than 5 [ 31 ]. In addition, the absorption, distribution, metabolism, and excretion (ADME) properties determine the pharmacokinetic parameters of the drugs by addressing their safety and efficacy [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

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Identification of Dietary Bioflavonoids as Potential Inhibitors against KRAS G12D Mutant—Novel Insights from Computer-Aided Drug Discovery

Ramalingam

Balakrishnan²,

Senthilnathan

et al. 2023

CIMB

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The KRAS G12D mutation is very frequent in many cancers, such as pancreatic, colon and lung, and has remained undruggable for the past three decades, due to its smooth surface and lack of suitable pockets. Recent small pieces of evidence suggest that targeting the switch I/II of KRAS G12D mutant could be an efficient strategy. Therefore, in the present study, we targeted the switch I (residues 25–40) and switch II (residues 57–76) regions of KRAS G12D with dietary bioflavonoids in comparison with the reference KRAS SI/II inhibitor BI-2852. Initially, we screened 925 bioflavonoids based on drug-likeness properties, and ADME properties and selected 514 bioflavonoids for further studies. Molecular docking resulted in four lead bioflavonoids, namely 5-Dehydroxyparatocarpin K (L1), Carpachromene (L2), Sanggenone H (L3), and Kuwanol C (L4) with binding affinities of 8.8 Kcal/mol, 8.64 Kcal/mol, 8.62 Kcal/mol, and 8.58 Kcal/mol, respectively, in comparison with BI-2852 (−8.59 Kcal/mol). Further steered-molecular dynamics, molecular-dynamics simulation, toxicity, and in silico cancer-cell-line cytotoxicity predictions significantly support these four lead bioflavonoids as potential inhibitors of KRAS G12D SI/SII inhibitors. We finally conclude that these four bioflavonoids have potential inhibitory activity against the KRAS G12D mutant, and are further to be studied in vitro and in vivo, to evaluate their therapeutic potential and the utility of these compounds against KRAS G12D mutated cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of Dietary Bioflavonoids as Potential Inhibitors against KRAS G12D Mutant—Novel Insights from Computer-Aided Drug Discovery

Ramalingam

Balakrishnan²,

Senthilnathan

et al. 2023

CIMB

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“…Nowadays, plant-based phytoconstituents such as polyphenols and flavonoids are attracting attention due to their versatile pharmacological activities such as antioxidants, anticancer, anti-inflammatory, etc (Kumar et al, 2013;Mishra et al, 2013;Ashokkumar, 2015;Tungmunnithum et al, 2018;Ashokkumar et al, 2022). The plant-derived compounds, individually or in combination with other drugs/compounds, are reported to work as HDAC inhibitors, HAT inhibitors, topoisomerase inhibitors, and other molecular target inhibitors of cancer and disease pathogenesis (Amin et al, 2009;Mekala et al, 2022). These compounds can scavenge various free radicals in the cells, reducing the cells' oxidative stress and metabolic burden and enhancing the production of antioxidant enzymes (Ramaiah et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and anticancer activities of Solanum nigrum Linn leaves

Bhuvaneshwari,

Ambiga

2022

J. Current Opinion Crop Sci.,

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Solanum nigrum Linn, belonging to the family Solanaceae, is a flowering species native to Australia, South Africa, and Asia. In the present study, the dried S. nigrum leaves were extracted with benzene, diethyl ether, and ethanol by Soxhlet’s extraction and screened qualitatively and quantitatively to determine their total phytoconstituent content and their potential antioxidant evaluation, followed by the GCMS analysis to predict the hit compounds. The highest amounts of phenols (120.50 mg), alkaloids (90.50 mg), and flavonoids (108.75 mg) were present in the diethyl ether extract of the Solanum nigrum leaves. In contrast, saponins (42.50g) are abundant in ethanol extract. The GCMS analysis of diethyl ether extract reported the top compounds with area %, height %, and specific retention times. The major compounds in the GCMS analysis are isopropyl myristate, octadecanedioic acid, and hexadecanedioic acid. Antioxidant assays such as the DPPH assay and reducing power assay revealed that the diethyl ether extract has more antioxidant activity than the standard itself. The two compounds from the GCMS study were then docked against an oncogene BRAF V600E and a mutated tumour suppressor gene p53 Y220C mutant. The results showed that the interaction was good and had higher negative binding energies. We report that S. nigrum leaves have potent antioxidant and anticancer properties.

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“…The physiochemical properties, drug likeness properties and the ADME properties of the compounds were evaluated using Molinspiration. For the molecular docking, the grid box was set with respected to the receptors and the energy minimized compounds were docked against those receptors with default parameters using Autodock software (28,29). The binding affinities of the protein-ligand complexes were evaluated and their binding energies were calculated.…”

Section: Molecular Modelling Studiesmentioning

confidence: 99%

Insilico evaluation of pharmacological activities of Kalarchi Chooranam

Vetriselvi¹,

Bharathajothi²

2023

IJAM

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The Indian traditional medicine practices such as siddha and ayurveda records various medicinal plants for the betterment of human health. Recent reports shows that this system of medicine has potential plants and formulation to treat various diseases and ailments. In the present study, we extracted and prepared the Kalarchi Chooranam of various ratios and chosen 4:1 ratio from our previous work. The aqueous extract of 4:1 ratio Kalarchi Chooranam was subjected to GCMS study and the compounds Inositol, Xanthosine (CAS), alpha.-D-Glucopyranoside, methyl 2,3-bis-O- were identified as lead 3 compounds. The Xanthosine (CAS), alpha.-D-Glucopyranoside, methyl 2,3-bis-O- have passed the drug likeness and ADME properties and further docked against various receptors involved in disease pathogenesis such as cancer (Bcl2, Bcl-X), PCOS (Cyp17, Follistatin), Inflammation & Analgesic (Cox1, Cox2), and Diabetics & Cardiovascular diseases (Er Alpha, Er Beta). The overall study reveals that the compounds have more binding affinities against the poly cystic ovarian syndrome receptors as the Xanthosine showed significant binding energies of -8.9 and -8.2 Kcal/mol and the Alpha.-D-Glucopyranoside, methyl 2,3-bis-O showed -8.2 and -9.7 Kcal/mol against CYP17 and Follistatin. The Kalarchi Chooranam has to be studied more reveal all its pharmacological activities.

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Synthesis, in vitro and structural aspects of cap substituted Suberoylanilide hydroxamic acid analogs as potential inducers of apoptosis in Glioblastoma cancer cells via HDAC /microRNA regulation

Cited by 16 publications

References 46 publications

Identification of Dietary Bioflavonoids as Potential Inhibitors against KRAS G12D Mutant—Novel Insights from Computer-Aided Drug Discovery

Identification of Dietary Bioflavonoids as Potential Inhibitors against KRAS G12D Mutant—Novel Insights from Computer-Aided Drug Discovery

Antioxidant and anticancer activities of Solanum nigrum Linn leaves

Insilico evaluation of pharmacological activities of Kalarchi Chooranam

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