Previously we have discovered a synthetically derived pyrrolidone alkaloid, MFM501, exhibiting good inhibitory activity against 53 MRSA and MSSA isolates with low cytotoxicity against three normal cell-lines with IC50 values at >625 µg/ml. Time-kill assay, scanning electron microscopy (SEM) analysis, in vivo oral acute toxicity test, and mice peritonitis model were carried out in this study. In the time-kill study, MFM501 showed a less than 3 log10 decrease in bacterial colony concentration value (CFU/ml) which represented a bacteriostatic action while displaying a time-dependent inhibitory mechanism. Following that, SEM analysis suggested that MFM501 may exert its inhibitory activity via cytoplasmic membrane disruption. Moreover, MFM501 showed no toxicity effect on treated mice at an estimated median acute lethal dose (LD50) value of more than 300 mg/kg and less than 2000 mg/kg. For the efficacy test, a mean effective dose (ED50) of 87.16 mg/kg was obtained via a single dose oral administration. Our data demonstrated that MFM501 has the potential to be developed further as a new, safe, and effective oral-delivered antibacterial agent against MRSA isolates.
The notable ability of human liver cytochrome P450 3A4 (CYP3A4) to metabolize diverse xenobiotics encourages researchers to explore in-depth the mechanism of enzyme action. Numerous CYP3A4 protein crystal structures have been deposited in protein data bank (PDB) and are majorly used in molecular docking analysis. The quality of the molecular docking results depends on the three-dimensional CYP3A4 protein crystal structures from the PDB. Present review endeavors to provide a brief outline of some technical parameters of CYP3A4 PDB entries as valuable information for molecular docking research. PDB entries between 22 April 2004 and 2 June 2021 were compiled and the active sites were thoroughly observed. The present review identified 76 deposited PDB entries and described basic information that includes CYP3A4 from human genetic, Escherichia coli (E. coli) use for protein expression, crystal structure obtained from X-ray diffraction method, taxonomy ID 9606, Uniprot ID P08684, ligand–protein structure description, co-crystal ligand, protein site deposit and resolution ranges between 1.7[Formula: see text]Å and 2.95[Formula: see text]Å. The observation of protein–ligand interactions showed the various residues on the active site depending on the ligand. The residues Ala305, Ser119, Ala370, Phe304, Phe108, Phe213 and Phe215 have been found to frequently interact with ligands from CYP3A4 PDB. Literature surveys of 17 co-crystal ligands reveal multiple mechanisms that include competitive inhibition, noncompetitive inhibition, mixed-mode inhibition, mechanism-based inhibition, substrate with metabolite, inducer, or combination modes of action. This overview may help researchers choose a trustworthy CYP3A4 protein structure from the PDB database to apply the protein in molecular docking analysis for drug discovery.
This study was part of our preliminary work in the search for biologically active compounds from endemic plants of Kuala Keniam National Park, Pahang, Malaysia. Postprandial hyperglycaemia is linked to the development of diabetes complications such as micro and macro vascular diseases. Inhibitions of carbohydrate digestive key enzymes, α-amylase and α-glucosidase using plant extracts are possible therapeutic strategies to suppress postprandial hyperglycaemia. The aim of this study was to investigate the effects of the dichloromethane leaf extract of Knema glauca (DLKG) in vitro and in vivo α-amylase and α-glucosidase inhibitory activities. The antidiabetic property of DLKG was investigated by using in vitro α-amylase and α-glucosidase inhibitory activity assays. The effects of DLKG on oral starch and sucrose challenge tests were investigated by administering 125, 250 and 500 mg/kg of the extract to normal and diabetic rats. DLKG demonstrated potent α-amylase and α-glucosidase inhibitory activities with IC50 values of 1.26 and 4.09 µg/ml, respectively. In the oral starch challenge test, the extract significantly (p<0.05) reduced blood glucose levels in both normal and diabetic rats. On the other hand, DLKG showed significant (p<0.05) reduction of blood glucose levels in normal rats in the oral sucrose challenge test. The results showed that the leaves of K. glauca possessed a beneficial effect in reducing postprandial hyperglycaemia and have potential as an alternative antidiabetic agent.
Five new isomeric polycyclic polyprenylated acylphloroglucinols (PPAPs) named mesuaferroic acid A, B, C, E and F (1-5) were isolated from ethyl acetate extract of Mesua ferrea L. (Clusiaceae). The isomeric compounds were obtained after extensive chromatographic procedures mainly using preparative HPLC. Structures were established after detailed spectroscopic analysis mostly by 2D NMR techniques. Compounds 4 and 5 exhibited good α-glucosidase inhibitory activity with IC 50 values of 0.43 and 0.60 mM, respectively, comparing to the positive control, 1-deoxynojirimycin (IC 50 0.63 mM).
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be one of the main causes of hospital-acquired infections in all regions of the world, while linezolid is one of the only commercially available oral antibiotics available against this dangerous gram-positive pathogen. In this study, the antibacterial activity from 32 analogues of synthetic gamma-lactam heterocycles against MRSA was determined. Amongst screened analogues for the minimum inhibitory concentration (MIC) assay, compound MFM514 displayed good inhibitory activity with MIC values of 7.8–15.6 µg/mL against 30 MRSA and 12 methicillin-sensitive S. aureus (MSSA) clinical isolates, while cytotoxicity evaluations displayed a mean inhibitory concentration (IC50) value of > 625 µg/mL, displaying a potential to becoming as a lead compound. In subsequent animal studies for MFM514, a single-dose oral acute toxicity test revealed an estimated mean lethal dose (LD50) value of <5000 mg/kg, while in the mice infection test, a mean effective dose (ED50) value of 29.39 mg/kg was obtained via oral administration. These results suggest that gamma-lactam carbon skeleton, particularly MFM514, is highly recommended to be evaluated further as a new safe and efficacious orally delivered antibacterial agent against MRSA.
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