Muchtaridi

A virtual screening approach for identifying plants with anti H5N1 neuraminidase activity

Recent outbreaks of highly pathogenic and occasional drug-resistant influenza strains have highlighted the need to develop novel anti-influenza therapeutics. Here, we report computational and experimental efforts to identify influenza neuraminidase inhibitors from among the 3000 natural compounds in the Malaysian-Plants Natural-Product (NADI) database. These 3000 compounds were first docked into the neuraminidase active site. The five plants with the largest number of top predicted ligands were selected for experimental evaluation. Twelve specific compounds isolated from these five plants were shown to inhibit neuraminidase, including two compounds with IC50 values less than 92 μM. Furthermore, four of the 12 isolated compounds had also been identified in the top 100 compounds from the virtual screen. Together, these results suggest an effective new approach for identifying bioactive plant species that will further the identification of new pharmacologically active compounds from diverse natural-product resources.

Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies

Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 μM. At 11.2 μM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.

Molecular Docking and 3D-Pharmacophore Modeling to Study the Interactions of Chalcone Derivatives with Estrogen Receptor Alpha

Tamoxifen is the most frequently used anti-estrogen adjuvant treatment for estrogen receptor-positive breast cancer. However, it is associated with an increased risk of several serious side–effects, such as uterine cancer, stroke, and pulmonary embolism. The 2′,4′-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) from plant leaves of Eugenia aquea, has been found to inhibit the proliferation of MCF-7 human breast cancer cells in a dose-dependent manner, with an IC50 of 74.5 μg/mL (250 μM). The aim of this work was to study the molecular interactions of new ChalcEA derivatives formed with the Estrogen Receptor α (ERα) using computer aided drug design approaches. Molecular docking using Autodock 4.2 was employed to explore the modes of binding of ChalcEA derivatives with ERα. The 3D structure-based pharmacophore model was derived using LigandScout 4.1 Advanced to investigate the important chemical interactions of the ERα-tamoxifen complex structure. The binding energy and the tamoxifen-pharmacophore fit score of the best ChalcEA derivative (HNS10) were −12.33 kcal/mol and 67.07 kcal/mol, respectively. The HNS10 interacted with Leu346, Thr347, Leu349, Ala350, Glu353, Leu387, Met388, Leu391, Arg394, Met421, and Leu525. These results suggest that the new ChalcEA derivatives could serve as the lead compound for potent ERα inhibitor in the fight against breast cancer.

Potential activity of some natural products compounds as Neuraminidase inhibitors based on molecular docking simulation and in vitro test

Neuraminidase (NA) plays an important role in replication and the release of a new avian influenza virion. In consequence, NA has been considered as a valid target in drug design against influenza virus. The aim of this study was to identify the new neuraminidase inhibitors using molecular docking simulation based on virtual screening from natural products compounds. The X-ray crystal structure of neuraminidase type N1 (PDB id: 3B7E) and N1 mutant (PDB id: 3NNS) using Autodock 4.2 program. Zanamivir was used as the control ligand and docked against neuraminidase type N1, further plotted between log IC50 value experiments of sialic acid derivatives compound versus log of Ki value of molecular docking. Molecular docking simulation was performed on 113 herb compounds along with zanamivir and oseltamivir as the control ligands. The result showed that the best interaction against of neuraminidase N1 and N1 mutant from herbs compound is katsumadain-A withfree energy value -7,54 kcal/mol and -7,46 kkal/mol, respectively. Katsumadain-Aformed hydrogen bond with amino acid residue Arg118 and Arg371 on neuraminidase and neuraminidase N1 mutant Katsumadain-A was also connected with Arg118 through hydrogen binding interaction. This in silico results also was proved by in vitro MUNANA assay.

HIGH PERFORMANCE LIQUID CHROMATOGRAPHY FOR α-MANGOSTIN ANALYSIS IN MANGOSTEEN PERICARP EXTRACT FOR ROUTINE ANALYSIS WITH PHOTODIODE ARRAY DETECTOR

The analytical methods for the standardization of α-mangostin are needed to set up a routine of a validated method for quality control of α-mangostin from Garcinia mangostana L. using HPLC methods. This study was aimed to validate the analytical method of High-Performance Liquid Chromatography (HPLC) for α-mangostin analysis with Photodiode Array (PDA). The analysis was conducted by HPLC with octadecyl silanol column, methanol and acetic acid 1% as a mobile phase and PDA detection at 243 nm. The coefficient correlation of analytical method was was 0.9999, the variation was less than 2%, LOD was 0.671 ppm, and LOQ was 2.174 ppm. The level of α-mangostin in mangosteen pericarp extract from Tasikmalaya was 8.56 ± 0.003%. The analytical method was met the validation criteria. The PDA sensitivity was 68.28% higher than UV-Vis detector.

The in Silico Study of Nutmeg Seeds (Myristica fragrans Houtt) as Peroxisome Proliferator Activated Receptor Gamma Activator Using 3D-QSAR Pharmacophore Modelling -

In this study, we created pharmacophore models from a dataset of agonists for PPAR gamma receptor using the Catalyst/Hypogen module. A training set consists of 22 compounds activity range between 0.1 to 3,500 nM, were carefully selected. In previous study, molecular docking of macelignan against PPARγ binding pocket showed a free energy binding of -11.07 kJ/mol, interaction with the hydrophobic pocket (diphenyl pocket) (Celik et al., 2007), and a hydrogen bond network (His323, Tyr473, His449 and Ser289) . The pharmacophore model (Hypo1), consisting of 5 features, i.e. one hydrogen bond acceptor (HBA), negative ionizable (NI), ring aromatic (RA) and two hydrophobics (HY) features, and one excluded volume. Hypo1 has the lowest total cost value (92.055), the highest cost difference (40,9316), the lowest RMSD (0.591049), and the best correlation coefficient (0.972949). Fourteen natural reported from nutmeg seeds (Myristica fragrans HOUTT.) were then mapped against Hypo1, and macelignan shows a fair fit value of 7.00102 with an estimated value of 1271.990 nM. This concludes, macelignant in nutmeg might have antidiabetic properties via PPARγ receptor activation.