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Fulltext In Vitro, In Silico and Network Pharmacology Mechanistic Approach to Investigate the α-Glucosidase Inhibitors Identified by Q-ToF-LCMS from Phaleria macrocarpa Fruit Subcritical CO2 Extract

Mia MAR, Ahmed QU, Ferdosh S, Helaluddin ABM, Awal MS, Sarian MN, et al.

Metabolites, 2022 Dec 15;12(12).
PMID: 36557305 DOI: 10.3390/metabo12121267

The fruit of Phaleria macrocarpa have been traditionally used as an antidiabetic remedy in Malaysia and neighbouring countries. Despite its potential for diabetes treatment, no scientific study has ever been conducted to predict the inhibitor interaction of the protein α-glucosidase identified in an extract prepared with a non-conventional extraction technique. Hence, the major aim of this research was to evaluate the in vitro antioxidant, the α-glucosidase inhibitors, and the molecular dynamic simulations of the α-glucosidase inhibitors identified by Quadrupole Time-of-Flight Liquid Chromatography Mass Spectrometry (Q-ToF-LCMS) analysis. Initially, dry fruit were processed using non-conventional and conventional extraction methods to obtain subcritical carbon dioxide extracts (SCE-1 and SCE-2) and heating under reflux extract (HRE), respectively. Subsequently, all extracts were evaluated for their in vitro antioxidative and α-glucosidase inhibitory potentials. Subsequently, the most bioactive extract (SCE-2) was subjected to Q-ToF-LCMS analysis to confirm the presence of α-glucosidase inhibitors, which were then analysed through molecular dynamic simulations and network pharmacology approaches to confirm their possible mechanism of action. The highest inhibitory effects of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and α-glucosidase on SCE-2 was found as 75.36 ± 0.82% and 81.79 ± 0.82%, respectively, compared to the SCE-1 and HRE samples. The Q-ToF-LCMS analysis tentatively identified 14 potent α-glucosidase inhibitors. Finally, five identified compounds, viz., lupenone, swertianolin, m-coumaric acid, pantothenic acid, and 8-C-glucopyranosyleriodictylol displayed significant stability, compactness, stronger protein-ligand interaction up to 100 ns further confirming their potential as α-glucosidase inhibitors. Consequently, it was concluded that the SCE-2 possesses a strong α-glucosidase inhibitory effect due to the presence of these compounds. The findings of this study might prove useful to develop these compounds as alternative safe α-glucosidase inhibitors to manage diabetes more effectively.
Fulltext Active site-specific quantum tunneling of hACE2 receptor to assess its complexing poses with selective bioactive compounds in co-suppressing SARS-CoV-2 influx and subsequent cardiac injury

Nipun TS, Ema TI, Mia MAR, Hossen MS, Arshe FA, Ahmed SZ, et al.

J Adv Vet Anim Res, 2021 Dec;8(4):540-556.
PMID: 35106293 DOI: 10.5455/javar.2021.h544

Objective: This research aims to study the target specificity of selective bioactive compounds in complexing with the human angiotensin-converting enzyme (hACE2) receptor to impede the severe acute respiratory syndrome coronavirus 2 influx mechanism resulting in cardiac injury and depending on the receptor's active site properties and quantum tunneling.
Materials and Methods: A library of 120 phytochemical ligands was prepared, from which 5 were selected considering their absorption, distribution, metabolism, and excretion (ADMET) and quantitative structure-activity relationship (QSAR) profiles. The protein active sites and belonging quantum tunnels were defined to conduct supramolecular docking of the aforementioned ligands. The hydrogen bond formation and hydrophobic interactions between the ligand-receptor complexes were studied following the molecular docking steps. A comprehensive molecular dynamic simulation (MDS) was conducted for each of the ligand-receptor complexes to figure out the values - root mean square deviation (RMSD) (Å), root mean square fluctuation (RMSF) (Å), H-bonds, Cα, solvent accessible surface area (SASA) (Å2), molecular surface area (MolSA) (Å2), Rg (nm), and polar surface area (PSA) (Å). Finally, computational programming and algorithms were used to interpret the dynamic simulation outputs into their graphical quantitative forms.
Results: ADMET and QSAR profiles revealed that the most active candidates from the library to be used were apigenin, isovitexin, piperolactam A, and quercetin as test ligands, whereas serpentine as the control. Based on the binding affinities of supramolecular docking and the parameters of molecular dynamic simulation, the strength of the test ligands can be classified as isovitexin > quercetin > piperolactam A > apigenin when complexed with the hACE2 receptor. Surprisingly, serpentine showed lower affinity (-8.6 kcal/mol) than that of isovitexin (-9.9 kcal/mol) and quercetin (-8.9 kcal/mol). The MDS analysis revealed all ligands except isovitexin having a value lower than 2.5 Ǻ. All the test ligands exhibited acceptable fluctuation ranges of RMSD (Å), RMSF (Å), H-bonds, Cα, SASA (Å2), MolSA (Å2), Rg (nm), and PSA (Å) values.
Conclusion: Considering each of the parameters of molecular optimization, docking, and dynamic simulation interventions, all of the test ligands can be suggested as potential targeted drugs in blocking the hACE2 receptor.
Oncoinformatic screening of the gene clusters involved in the HER2-positive breast cancer formation along with the in silico pharmacodynamic profiling of selective long-chain omega-3 fatty acids as the metastatic antagonists

Morshed AKMH, Al Azad S, Mia MAR, Uddin MF, Ema TI, Yeasin RB, et al.

Mol Divers, 2023 Dec;27(6):2651-2672.
PMID: 36445532 DOI: 10.1007/s11030-022-10573-8

The HER2-positive patients occupy ~ 30% of the total breast cancer patients globally where no prevalent drugs are available to mitigate the frequent metastasis clinically except lapatinib and neratinib. This scarcity reinforced researchers' quest for new medications where natural substances are significantly considered. Valuing the aforementioned issues, this research aimed to study the ERBB2-mediated string networks that work behind the HER2-positive breast cancer formation regarding co-expression, gene regulation, GAMA-receptor-signaling pathway, cellular polarization, and signal inhibition. Following the overexpression, promotor methylation, and survivability profiles of ERBB2, the super docking position of HER2 was identified using the quantum tunneling algorithm. Supramolecular docking was conducted to study the target specificity of EPA and DHA fatty acids followed by a comprehensive molecular dynamic simulation (100 ns) to reveal the RMSD, RMSF, Rg, SASA, H-bonds, and MM/GBSA values. Finally, potential drug targets for EPA and DHA in breast cancer were constructed to determine the drug-protein interactions (DPI) at metabolic stages. Considering the values resulting from the combinational models of the oncoinformatic, pharmacodynamic, and metabolic parameters, long-chain omega-3 fatty acids like EPA and DHA can be considered as potential-targeted therapeutics for HER2-positive breast cancer treatment.
Baicalein as Promising Anticancer Agent: A Comprehensive Analysis on Molecular Mechanisms and Therapeutic Perspectives

Morshed AKMH, Paul S, Hossain A, Basak T, Hossain MS, Hasan MM, et al.

Cancers (Basel), 2023 Apr 03;15(7).
PMID: 37046789 DOI: 10.3390/cancers15072128

Despite significant therapeutic advancements for cancer, an atrocious global burden (for example, health and economic) and radio- and chemo-resistance limit their effectiveness and result in unfavorable health consequences. Natural compounds are generally considered safer than synthetic drugs, and their use in cancer treatment alone, or in combination with conventional therapies, is increasingly becoming accepted. Interesting outcomes from pre-clinical trials using Baicalein in combination with conventional medicines have been reported, and some of them have also undergone clinical trials in later stages. As a result, we investigated the prospects of Baicalein, a naturally occurring substance extracted from the stems of Scutellaria baicalensis Georgi and Oroxylum indicum Kurz, which targets a wide range of molecular changes that are involved in cancer development. In other words, this review is primarily driven by the findings from studies of Baicalein therapy in several cancer cell populations based on promising pre-clinical research. The modifications of numerous signal transduction mechanisms and transcriptional agents have been highlighted as the major players for Baicalein's anti-malignant properties at the micro level. These include AKT serine/threonine protein kinase B (AKT) as well as PI3K/Akt/mTOR, matrix metalloproteinases-2 & 9 (MMP-2 & 9), Wnt/-catenin, Poly(ADP-ribose) polymerase (PARP), Mitogen-activated protein kinase (MAPK), NF-κB, Caspase-3/8/9, Smad4, Notch 1/Hes, Signal transducer and activator of transcription 3 (STAT3), Nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap 1), Adenosine monophosphate-activated protein kinase (AMPK), Src/Id1, ROS signaling, miR 183/ezrin, and Sonic hedgehog (Shh) signaling cascades. The promise of Baicalein as an anti-inflammatory to anti-apoptotic/anti-angiogenic/anti-metastatic medicinal element for treating various malignancies and its capability to inhibit malignant stem cells, evidence of synergistic effects, and design of nanomedicine-based drugs are altogether well supported by the data presented in this review study.