Marantodes pumilum: Systematic computational approach to identify their therapeutic potential and effectiveness

Azfaralariff, Ahmad; Farahfaiqah, Fazial; Shahid, M. Khan; Sanusi, Siti Aisyah; Law, Douglas; Isa, Abdul Razak Mohd; Muhamad, Mustadza; Tsui, Tee Thiam; Fazry, Shazrul

doi:10.1016/j.jep.2021.114751

Cited by 17 publications

(9 citation statements)

References 56 publications

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“…The cytotoxic property of GAECE was evaluated using the SRB assay, as previously described by Azfaralariff et al . (2022). A density of 1 × 10 4 of L6 rat muscle cells was seeded in a 96‐well plate and maintained in DMEM medium supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…Over the past decade, computer‐aided drug discovery (CADD) has been widely employed in the identification of promising therapeutic drugs for various illnesses. Using computational methods before wet‐lab experiments speeds up drug discovery, reduces costs, and lowers risks (Azfaralariff et al ., 2022). The potential of G. atroviridis fruit ethanolic crude extract (GAECE) to alleviate DM has not been investigated or reported yet.…”

Section: Introductionmentioning

confidence: 99%

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Antidiabetic potential of ethanolic crude extract of Garcinia atroviridis fruits: in vitro, in ovo, and in silico analysis

Shahid,

Fazry,

Najm

et al. 2024

Int J of Food Sci Tech

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SummaryVarious parts of Garcinia atroviridis have long been used to address various health issues and as a seasoning. Past research has highlighted the leaf extracts' diverse medicinal properties, including antioxidant, antihyperlipidaemic, antibacterial, antitumor, anti‐inflammatory, and antifungal effects. No research has explored the therapeutic effects of the ethanolic crude extract of G. atroviridis fruits (GAECE) for diabetes. This study aims to assess GAECE's antidiabetic potential using various methods, including in vitro and in ovo assays, cytotoxicity testing, phytochemical profiling, and in silico analysis to identify active compounds. The GAECE was prepared using the maceration method and evaluated for its inhibitory effect against DPP‐4, α‐glucosidase, and α‐amylase enzyme activities. The glucose uptake potential and the kinetic study of glucose uptake were performed to determine the time required to exert its glucose uptake potential. Moreover, the antihyperglycaemic effect was evaluated in diabetes induced in ovo model. Q‐TOF LCMS was performed to identify the phytochemical, which was then subjected to molecular docking and molecular dynamics (MD) simulation was conducted for 100 nanoseconds to validate the ligand–receptor complexes. GAECE exhibited promising antidiabetic potential, with half maximal inhibitory concentrations (IC50) of 0.129 ± 0.002 mg mL−1 for α‐amylase and 0.593 ± 0.01 mg mL−1 for α‐glucosidase; and showed an inhibition of 70.07 ± 0.96% for DPP‐4 enzymes at 0.5 mg mL−1. The 50% cell viability was found to be 0.87 ± 0.08 mg mL−1, 0.76 ± 0.04 mg mL−1, and 0.66 ± 0.03 mg mL−1 for 24, 48, and 72 h of treatment, respectively. Furthermore, GAECE showed potential for glucose uptake in differentiated L6 cells, resulting in a 136.7 ± 1.2% increase in glucose uptake. Kinetic analysis revealed peak potential at 10 min at the concentration of 0.4 mg mL−1. In in ovo diabetes induced model, GAECE reduced blood plasma glucose levels (152.4 ± 0.52 mg dL−1), which was similar to the effect of insulin.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antidiabetic potential of ethanolic crude extract of Garcinia atroviridis fruits: in vitro, in ovo, and in silico analysis

Shahid,

Fazry,

Najm

et al. 2024

Int J of Food Sci Tech

Self Cite

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“…The experiment is carried out computationally and is called the “ in silico method.” These methods use databases, network analysis, and machine learning approaches that are faster, more critical, and more cost-effective than in vitro and in vivo studies ( Azfaralariff et al, 2022 ). Therefore, in the present study, to identify the high-risk deleterious variations, the functional annotation of missense variations in the CYP1B1 gene was carried out by employing multiple bioinformatics tools.…”

Section: Methodsmentioning

confidence: 99%

“…On top of that, the protein-protein interaction (PPI) of CYP1B1 was also determined by utilizing the STRING protein database ( https://string-db.org/ ). The STRING database query terms were cut-off at 0.7 and the maximum additional interaction was 10 ( Azfaralariff et al, 2022 ; Szklarczyk et al, 2021 ). Cytoscape software version 3.8.2 ( https://cytoscape.org/ ) was employed to construct the highly co-expressed genes and PPI networks in the present study ( Shannon et al, 2003 ).…”

Section: Methodsmentioning

confidence: 99%

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Shahid

Azfaralariff

Tufail

et al. 2022

PeerJ

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Background Primary congenital glaucoma (PCG) is the most common subtype of glaucoma caused by defects in the cytochrome P450 1B1 (CYP1B1) gene. It is developing among infants in more than 80% of cases who exhibit impairments in the anterior chamber angle and the trabecular meshwork. Thus, a comprehensive in silico approach was performed to evaluate the effect of high-risk deleterious missense variations in the CYP1B1 gene. Material and methods All the information for CYP1B1 missense variants was retrieved from the dbSNP database. Seven different tools, namely: SIFT, PolyPhen-2, PROVEAN, SNAP2, PANTHER, PhD-SNP, and Predict-SNP, were used for functional annotation, and two packages, which were I-Mutant 2.0 and MUpro, were used to predict the effect of the variants on protein stability. A phylogenetic conservation analysis using deleterious variants was performed by the ConSurf server. The 3D structures of the wild-type and mutants were generated using the I-TASSER tool, and a 50 ns molecular dynamic simulation (MDS) was executed using the GROMACS webserver to determine the stability of mutants compared to the native protein. Co-expression, protein-protein interaction (PPI), gene ontology (GO), and pathway analyses were additionally performed for the CYP1B1 in-depth study. Results All the retrieved data from the dbSNP database was subjected to functional, structural, and phylogenetic analysis. From the conducted analyses, a total of 19 high-risk variants (P52L, G61E, G90R, P118L, E173K, D291G, Y349D, G365W, G365R, R368H, R368C, D374N, N423Y, D430E, P442A, R444Q, F445L, R469W, and C470Y) were screened out that were considered to be deleterious to the CYP1B1 gene. The phylogenetic analysis revealed that the majority of the variants occurred in highly conserved regions. The MD simulation analysis exhibited that all mutants’ average root mean square deviation (RMSD) values were higher compared to the wild-type protein, which could potentially cause CYP1B1 protein dysfunction, leading to the severity of the disease. Moreover, it has been discovered that CYP1A1, VCAN, HSD17B1, HSD17B2, and AKR1C3 are highly co-expressed and interact with CYP1B1. Besides, the CYP1B1 protein is primarily involved in the metabolism of xenobiotics, chemical carcinogenesis, the retinal metabolic process, and steroid hormone biosynthesis pathways, demonstrating its multifaceted and important roles. Discussion This is the first comprehensive study that adds essential information to the ongoing efforts to understand the crucial role of genetic signatures in the development of PCG and will be useful for more targeted gene-disease association studies.

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“…The detailed results of P2RANK are tabulated in Supplementary Table S1. The AutoDock Vina tool was utilized to execute molecular docking simulations due to its rapid, stochastic optimizations by operating multiple CPU cores, which allowed it to overcome the confines of the maximum number of rotatable bonds, atoms, and grid map size [35][36][37]. Docking grids of all macromolecule receptors were adjusted into squares of 24 Å with x, y, and z coordinates of −21.7641, 33.6885, and −18.7002 for Cystathionine gamma-lyase; −35.004, −20.3346, and −41.463 for 3-mercaptopyruvate sulfurtransferase; and −9.2621, 22.9917, and −18.5675 for Cystathionine beta-synthase, respectively, to define the ligand binding sites.…”

Section: Druggable Pockets and Molecular Docking Analysismentioning

confidence: 99%

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression

Khan

Wang

et al. 2022

Molecules

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Hydrogen sulfide (H2S), a gaseous signaling molecule, is associated with the development of various malignancies via modulating various cellular signaling cascades. Published research has established the fact that inhibition of endogenous H2S production or exposure of H2S donors is an effective approach against cancer progression. However, the effect of pharmacological inhibition of endogenous H2S-producing enzymes (cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST)) on the growth of breast cancer (BC) remains unknown. In the present study, DL-propargylglycine (PAG, inhibitor of CSE), aminooxyacetic acid (AOAA, inhibitor of CBS), and L-aspartic acid (L-Asp, inhibitor of 3-MPST) were used to determine the role of endogenous H2S in the growth of BC by in vitro and in vivo experiments. An in silico study was also performed to confirm the results. Corresponding to each enzyme in separate groups, we treated BC cells (MCF-7 and MDA-MB-231) with 10 mM of PAG, AOAA, and L-Asp for 24 h. Findings reveal that the combined dose (PAG + AOAA + L-Asp) group showed exclusive inhibitory effects on BC cells’ viability, proliferation, migration, and invasion compared to the control group. Further, treated cells exhibited increased apoptosis and a reduced level of phospho (p)-extracellular signal-regulated protein kinases such as p-AKT, p-PI3K, and p-mTOR. Moreover, the combined group exhibited potent inhibitory effects on the growth of BC xenograft tumors in nude mice, without obvious toxicity. The molecular docking results were consistent with the wet lab experiments and enhanced the reliability of the drugs. In conclusion, our results demonstrate that the inhibition of endogenous H2S production can significantly inhibit the growth of human breast cancer cells via the AKT/PI3K/mTOR pathway and suggest that endogenous H2S may act as a promising therapeutic target in human BC cells. Our study also empowers the rationale to design novel H2S-based anti-tumor drugs to cure BC.

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Marantodes pumilum: Systematic computational approach to identify their therapeutic potential and effectiveness

Cited by 17 publications

References 56 publications

Antidiabetic potential of ethanolic crude extract of Garcinia atroviridis fruits: in vitro, in ovo, and in silico analysis

Antidiabetic potential of ethanolic crude extract of Garcinia atroviridis fruits: in vitro, in ovo, and in silico analysis

Screening of high-risk deleterious missense variations in the CYP1B1 gene implicated in the pathogenesis of primary congenital glaucoma: A comprehensive in silico approach

Pharmacological Inhibition of Endogenous Hydrogen Sulfide Attenuates Breast Cancer Progression

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