Probing the polyphenolic flavonoid, morin as a highly efficacious inhibitor against amyloid(A4V) mutant SOD1 in fatal amyotrophic lateral sclerosis

Srinivasan, E.; Chandrasekhar, G.; Rajasekaran, R.

doi:10.1016/j.abb.2022.109318

Cited by 7 publications

(3 citation statements)

References 114 publications

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“…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 ]. Our results revealed that all our four leads showed excellent binding energies (in the range of −8.8 to −8.5) and Ki values (ranging from 0.83 to 28.54 µM), in comparison with the KRAS switch I/II inhibitor BI-2852, which showed a binding energy of −8.59 Kcal/mol and Ki value of 3.69 µM, as shown in Table 3 .…”

Section: Discussionmentioning

confidence: 99%

“…In simple words, the larger the energy spent to pull out the ligand, the higher the protein—ligand affinity, and the less the energy spent to pull out the ligand, the less the protein—ligand affinity. The steered molecular dynamics (SMD) of the top 4 lead flavonoids filtered from the above studies, along with the BI-2852 (KRAS switch I/II pocket inhibitor) was performed using YASARA software [ 34 ] ( (accessed on 23 December 2022)). At 298K and 7 pH, the amber force field with a water-filled cubic box with 0.997 g/mL solvent density, 0.9% NaCl, and 75 Å × 75 Å × 75 Å as x, y, and z dimensions was constructed [ 35 ].…”

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: Methodsmentioning

confidence: 99%

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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“…Srinivasan et al studied the effectiveness of flavonoids against amyloids, such as morin, myricetin, and epigallocatechin gallate. Additionally, it was determined that morin has a significant therapeutic potential for developing extremely effective inhibitors for reducing deadly and incurable ALS ( Srinivasan et al, 2022b ).…”

Section: Phytoconstituents In Different Neurological Disordersmentioning

confidence: 99%

Natural product-based pharmacological studies for neurological disorders

Puri

Kanojia²,

Sharma³

et al. 2022

Front. Pharmacol.

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Central nervous system (CNS) disorders and diseases are expected to rise sharply in the coming years, partly because of the world’s aging population. Medicines for the treatment of the CNS have not been successfully made. Inadequate knowledge about the brain, pharmacokinetic and dynamic errors in preclinical studies, challenges with clinical trial design, complexity and variety of human brain illnesses, and variations in species are some potential scenarios. Neurodegenerative diseases (NDDs) are multifaceted and lack identifiable etiological components, and the drugs developed to treat them did not meet the requirements of those who anticipated treatments. Therefore, there is a great demand for safe and effective natural therapeutic adjuvants. For the treatment of NDDs and other memory-related problems, many herbal and natural items have been used in the Ayurvedic medical system. Anxiety, depression, Parkinson’s, and Alzheimer’s diseases (AD), as well as a plethora of other neuropsychiatric disorders, may benefit from the use of plant and food-derived chemicals that have antidepressant or antiepileptic properties. We have summarized the present level of knowledge about natural products based on topological evidence, bioinformatics analysis, and translational research in this review. We have also highlighted some clinical research or investigation that will help us select natural products for the treatment of neurological conditions. In the present review, we have explored the potential efficacy of phytoconstituents against neurological diseases. Various evidence-based studies and extensive recent investigations have been included, which will help pharmacologists reduce the progression of neuronal disease.

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Defensin-based therapeutic peptide design in attenuating V30M TTR-induced Familial Amyloid Polyneuropathy

Chandrasekhar,

Pengyong,

Pravallika

et al. 2023

3 Biotech

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Probing the polyphenolic flavonoid, morin as a highly efficacious inhibitor against amyloid(A4V) mutant SOD1 in fatal amyotrophic lateral sclerosis

Cited by 7 publications

References 114 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

Natural product-based pharmacological studies for neurological disorders

Defensin-based therapeutic peptide design in attenuating V30M TTR-induced Familial Amyloid Polyneuropathy

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