Co-reporter:Zhi Siang Toh, Hongyu Wang, Yew Mun Yip, Yuyun Lu, Benedict Jeffrey Ang Lim, Daiwei Zhang, Dejian Huang
Bioorganic & Medicinal Chemistry 2015 Volume 23(Issue 24) pp:7641-7649
Publication Date(Web):15 December 2015
DOI:10.1016/j.bmc.2015.11.008
A high throughput assay was applied to guide the isolation of a new pancreatic α-amylase inhibitor, dracoflavan B, from the dragon’s blood resin from Daemonorops draco. Applying C18 column, we successfully isolated both diastereomers and their structures verified by 1H NMR spectra in comparison with the literature values. Their activity in inhibition of pancreatic α-amylase with comparable IC50 values of 23 μM (A type) and 27 μM (B type) that are similar to that of acarbose. Dracoflavan B shows much weaker activity in inhibiting bacterial α-amylase and no activity towards fungal α-amylase. Moreover, both isomers show no inhibitory activity towards mammalian α-glucosidase. Kinetic analysis revealed that using starch as the substrate, dracoflavan B was a non-competitive α-amylase inhibitor with a Ki value of 11.7 μM. Lack of α-amylase inhibition for proanthocyanidin A2 dimer demonstrated that dracoflavan B hydrophobic nature of the B, A′, C′ and B′ rings are important for its α-amylase inhibition. In addition, selective chemical modification studies revealed that the phenolic group is also vital to dracoflavan B for its pancreatic α-amylase inhibition activity. Without the A ring phenolic hydrogen bond donor, the derivatives of dracoflavan B showed detrimental α-amylase inhibition. On the contrary, galloylation on the A ring phenolic OH group enhanced the activity as shown by the low IC50 (12 μM) against α-amylase which is 56% more potent as compared to dracoflavan B.
Co-reporter:Mohamed Rashid Asyifah, Kaihui Lu, Hui Lin Ting, and Dawei Zhang
Journal of Agricultural and Food Chemistry 2014 Volume 62(Issue 16) pp:3505-3516
Publication Date(Web):March 26, 2014
DOI:10.1021/jf5007352
The array of comorbidities that comes with obesity and the propelling surge of this disease globally today make the urgent need for treatment vital. Although promoting a healthy physical regimen and controlled diet to affected patients are the main bulk of present treatment, prescriptions of weight-loss medications have also been introduced to complement this treatment. However, the use of synthetic medications may produce adverse side effects and consequently affect the patient’s quality of life. In view of these problems, the use of natural sources as alternative remedies has recently become very popular. Tropical fruit “waste components”, namely, the seed, flower, leaf, peel, and part of the fruit, which are often discarded after consumption, have recently been studied and showed evidence suggesting their potential as promising future alternative sources of remedy. The high amounts of phytochemicals present in these components were believed to be responsible for the antiobesity effect observed experimentally. This review aims to introduce some of the recently discussed tropical fruit waste components that have been discovered to possess antiobesity effects. The major bioactive compounds of the respective fruit components identified and deduced to be responsible for the overall bioactivity will be evaluated. Following this, the subsequent need for the development of an effective processing or recycling technique required to effectively tap the maximum potential of these fruit parts will also be addressed.
Co-reporter:Jintao Wang, Kaihui Lu, Shuguang Xuan, Zaozhen Toh, Dawei Zhang and Fangwei Shao
Chemical Communications 2013 vol. 49(Issue 42) pp:4758-4760
Publication Date(Web):03 Apr 2013
DOI:10.1039/C3CC40868J
A new G-quadruplex (GQ) stabilizer, [Pt(Dip)2](PF6)2 (Dip: 4,7-diphenyl-1,10-phenanthroline), is prepared by the microwave irradiation method. The complex can highly stabilize G-quadruplex, but has negligible interactions with duplex DNA. Aromatic anchors on the polypyridyl ligands bestow the stabilizer with a high binding preference towards parallel GQ.
Co-reporter:Kaihui Lu, Miaomiao Han, Hui Lin Ting, Zeyu Liu, and Dawei Zhang
Journal of Natural Products 2013 Volume 76(Issue 4) pp:672-678
Publication Date(Web):March 22, 2013
DOI:10.1021/np300889y
Adipocyte dysfunction is a major cause of obesity, which is associated strongly with many disorders including psychological and medical morbidities, metabolic abnormalities, and cardiovascular diseases as well as a series of cancers. This study investigated the antiadipogenic activity of scutellarin (1) in 3T3-L1 preadipocytes as well as the underlying molecular mechanisms. It was observed that 1 reduced adipocyte differentiation of 3T3-L1 cells potently, as evidenced by a decrease in cellular lipid accumulation. At the molecular level, mRNA expression of the master adipogenic transcription factors, PPARγ and C/EBPα, was decreased markedly. However, mRNA levels of C/EBPβ, the upstream regulator of PPARγ and C/EBPα, were not decreased by 1. Moreover, a dose-dependent upregulation of PPARα was observed for 1. Computational modeling indicated that 1 can bind to PPARα, γ, and δ each in a distinct manner, while it can activate PPARα only by forming a hydrogen bond with Y464, thus stabilizing the AF-2 helix and activating PPARα. Therefore, these results suggest that 1, a major component of Scutellaria baicalensis, attenuates fat cell differentiation by upregulating PPARα as well as downregulating the expression of PPARγ and C/EBPα, thus showing therapeutic potential for obesity-related diseases.
Co-reporter:Hema Malani and Dawei Zhang
The Journal of Physical Chemistry A 2013 Volume 117(Issue 16) pp:3521-3528
Publication Date(Web):March 29, 2013
DOI:10.1021/jp4007697
We have investigated the mechanism of alkali metal incorporation into C60 fullerene by density functional theory (DFT) at the UB3LYP/6-31G* level of theory. Calculations were performed to study the insertion pathways of Li+, Na+, and K+ through six- or five-membered rings of fullerene, and the computed energy barriers of metal ion insertion are compared with the available experimental data. Between the two possible insertion pathways, metal ion insertion through [2 + 2 + 2] ring opening of the six-membered ring is found to be more favored than the insertion through the ring opening of the five-membered ring. The size of the ring openings generated by the three metal ions is likely to be correlated with their ionic size, which shows the smallest opening for Li+ and the largest for K+ cation. The insertion energy barriers of the ions are found to be increased in the order of Li+ < Na+ < K+ in line with the experimental results. The ring opening made by breaking of C–C bonds during the metal ion insertion in six- or five-membered rings can cause the ring to be rearranged and convert back into a closed fullerene cage to form a stable endohedral metal-fullerene complex.
Co-reporter:Yossa Dwi Hartono, Raudah Lazim, Yew Mun Yip, Dawei Zhang
Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 4) pp:1695-1700
Publication Date(Web):15 February 2012
DOI:10.1016/j.bmcl.2011.12.105
Antibodies HK20 and D5 have been shown to target HIV-1 gp41, thereby inhibiting membrane fusion that facilitates viral entry. The binding picture is static, based on the X-ray crystal structures of the Fab regions and gp41 mimetic five-helix bundle. In this study, we carried out molecular dynamics simulation to provide the dynamic binding picture. Calculated binding free energies are within reasonable range of and follow the trend of the experimental values: −15.28 kcal/mol for HK20 Fab (expt. −11.60 kcal/mol) and −17.90 kcal/mol for D5 Fab (expt. −11.70 kcal/mol). Alanine scanning at protein–protein interface reveals that the highest contributors to binding for HK20 Fab are F54 and I56, both of VH region, as well as R30′ of VL region; whereas for D5 Fab, F54 of VH region, as well as W32′ and Y94′ of VL region. HK20 F54 and I56, as well as D5 I52, F54, and T56, bind to the gp41 hydrophobic binding pocket, an important region targeted by many other fusion inhibitors. Hydrogen bonding analysis also identifies high-occupancy hydrogen bonds at the periphery of gp41 hydrophobic pocket. Considering that almost all interface residues are turn residues, further work may be directed to turn mimics. Pre-orientation by the hydrogen bonds to poise this particular turn towards the binding pocket may also be a point worth pursuing.
Co-reporter:Zhijun Xu, Raudah Lazim, Ye Mei, Dawei Zhang
Chemical Physics Letters 2012 s 539–540() pp: 239-244
Publication Date(Web):
DOI:10.1016/j.cplett.2012.05.025
Co-reporter:Yossa Dwi Hartono, Angelina Noviani Lee, Sylvia Lee-Huang, Dawei Zhang
Bioorganic & Medicinal Chemistry Letters 2011 Volume 21(Issue 6) pp:1607-1611
Publication Date(Web):15 March 2011
DOI:10.1016/j.bmcl.2011.01.121
HL9 is a nonapeptide fragment of human lysozyme which has been shown to have anti-HIV-1 activity in nanomolar concentration. This study aims to explain this inhibitory activity by using molecular dynamics (MD) simulation, focusing on the ectodomain of gp41, the envelope glycoprotein of HIV-1 crucial to membrane fusion. It was found that in HL9, two Trp residues separated by two others occupy the conserved hydrophobic pocket on gp41 and thus inhibit fusion in dominant-negative manner. Detailed HL9-gp41 binding interactions and free energies of binding were obtained through MD simulation and solvated interaction energies (SIE) calculation, giving a binding free energy of −8.25 kcal/mol which is in close agreement with the experimental value of −9.96 kcal/mol. Since C-helical region (C34) of gp41 also has two Trp residues separated by two others, this arrangement may be generalised and used to scan peptide library and to find those having similar manner of inhibition.
Co-reporter:Dr. Bengang Xing;Tingting Jiang;Dr. Xiangyang Wu;Roushen Liew;Jie Zhou;Dr. Dawei Zhang;Dr. Edwin K. L. Yeow
Chemistry - A European Journal 2011 Volume 17( Issue 50) pp:14170-14177
Publication Date(Web):
DOI:10.1002/chem.201102195
Abstract
The molecular interactions of the glycopeptide antibiotic vancomycin (Van) with bacterial cell wall analogues N,N′-diacetyl-L-Lys-D-Ala-D-Ala (Ac2KdAdA) and N,N′-diacetyl-L-Lys-D-Ala-D-Lac (Ac2KdAdL) were investigated in neat water, phosphate buffer and HEPES buffer by using fluorescence correlation spectroscopy (FCS) and molecular dynamics (MD) simulations. The FCS determined dissociation constants (kd) show that the intrinsic binding affinity between Van and the drug-sensitive peptide ligand Ac2KdAdA remains invariant when the solvent is changed from neat water to either PBS or HEPES buffer; this demonstrates that there are no obvious solvent effects on the association between Van and Ac2KdAdA due to the strong intermolecular interaction between the two moieties. When compared to Ac2KdAdA, a significantly larger kd value was observed for the binding between the drug-resistant peptide ligand Ac2KdAdL and Van. Furthermore, the kd increased by about 8- to 11-times when the solvent was changed from neat water to 10 mM phosphate/HEPES buffer. The stability of the Ac2KdAdL–Van complex was dependent on the concentration of the buffer and kd increases as the concentration of either phosphate ions or HEPES increased until an equilibrium was attained. Both FCS and MD simulation studies clearly showed that the components constituting the buffer solution (e.g., phosphate ions and HEPES) are involved in molecular interactions with the binding pocket of Van and they profoundly affect the intrinsic stability of the complex formed between the low-affinity Ac2KdAdL and Van. These results could help us to better understand the detailed structure and activity of glycopeptide antibiotic derivatives toward bacterial cell wall peptide analogues, and can further facilitate the development of new drug candidates against drug-resistant bacterial strains.
Co-reporter:Angelina Noviani Lee;Yossa Dwi Hartono;Tiedong Sun
Journal of Molecular Modeling 2011 Volume 17( Issue 7) pp:1635-1641
Publication Date(Web):2011 July
DOI:10.1007/s00894-010-0867-5
Molecular dynamics (MD) simulations were carried out to study the behavior of human receptor molecule in the hemagglutinin (HA) of 1918 and 2009 H1N1 influenza viruses respectively. The 2009 HA model was obtained by virtually mutating the 1918 HA crystal structure based on A/Mexico City/MCIG01/2009(H1N1) segment 4 sequence. We found that human receptor molecule has no binding preference between the 2009 HA and the 1918 HA. In addition, among the four sugar moieties in the human receptor molecule, sialic acid contributes the most to the electrostatic and non-polar interaction energy during binding. Furthermore, the hydrogen bonds between sialic acid and the surrounding residues in 1918 HA are preserved in 2009 HA. We also found that the mutated residues contribute to a more favorable binding of hemagglutinin to the human receptor molecule.
Co-reporter:Ye Mei;LiLi Duan;QingGang Zhang
Science China Chemistry 2011 Volume 54( Issue 12) pp:1974-1981
Publication Date(Web):2011 December
DOI:10.1007/s11426-011-4399-3
In this study, we apply both pairwise AMBER03 force field and the recently developed polarized force field to study the folding process of EK peptide under various ion strength and pH conditions. The polarized force field is based on our newly proposed adaptive hydrogen bond-specific charge (AHBC) scheme. These two force fields differ only by the atomic charges. Solvent effect is described with generalized Born models (IGB5 in AMBER 10 package). The result shows that although when applying AMBER03 charge, the helical structure is preferred, its dependence on salt concentration and pH is qualitatively wrong. While using AHBC the peptide finds its native structure within 10 ns, and then fluctuates around this folded state. Under high salt concentration or extreme pH conditions the calculated helical structure probability drops, which is in qualitative agreement with the experiment. Analysis of the atomic charges and the interaction between the donor-acceptor pair in main hydrogen bonds shows that the helical structure is stabilized when polarization effect is counted. It again shows that polarization effect is a very important improvement over traditional force field and is essential for protein folding. We also prove that the salt bridge interaction between 4-residue apart GLU and LYS residues is not critical to the stability of helical structure of EK peptide, but is merely an auxiliary factor, also in agreement with the experiment.
Co-reporter:Caiyi Wei, Ye Mei, Dawei Zhang
Chemical Physics Letters 2010 Volume 495(1–3) pp:121-124
Publication Date(Web):29 July 2010
DOI:10.1016/j.cplett.2010.06.048
Abstract
Molecular dynamics studies of 5CITEP binding with HIV-1 integrase (IN) are presented using both polarized and nonpolarized force fields. When nonpolarized force field is used, the ligand drifts away from the original binding site. However, this depressing behavior can be curbed by introducing electronic polarization effect into the force field that stabilizes the protein structure and keeps the ligand in the binding pocket. Moreover, simulation under polarized force field gives a binding energy of −4.85 kcal/mol which is in excellent agreement with the experimental ΔG of −4.38 kcal/mol. The results demonstrate the importance of intra-protein electronic polarization in stabilizing the binding complex of IN–5CITEP and accurately predicting the binding energy.
Co-reporter:Zhijun Xu, Ye Mei, Lili Duan, Dawei Zhang
Chemical Physics Letters 2010 Volume 495(1–3) pp:151-154
Publication Date(Web):29 July 2010
DOI:10.1016/j.cplett.2010.06.073
Abstract
Three novel schemes on the basis of newly developed polarized protein-specific charge (PPC) have been proposed to refine the structure of staphylococcal nuclease generated by AMBER simulation. The performance of the refinement is analyzed in term of the stability and the recovery of intra-protein hydrogen bonds.
Co-reporter:Jintao Wang, Kaihui Lu, Shuguang Xuan, Zaozhen Toh, Dawei Zhang and Fangwei Shao
Chemical Communications 2013 - vol. 49(Issue 42) pp:NaN4760-4760
Publication Date(Web):2013/04/03
DOI:10.1039/C3CC40868J
A new G-quadruplex (GQ) stabilizer, [Pt(Dip)2](PF6)2 (Dip: 4,7-diphenyl-1,10-phenanthroline), is prepared by the microwave irradiation method. The complex can highly stabilize G-quadruplex, but has negligible interactions with duplex DNA. Aromatic anchors on the polypyridyl ligands bestow the stabilizer with a high binding preference towards parallel GQ.
![6A-[(2-aminoethyl)amino]-6A-deoxy- beta-Cyclodextrin](http://img.cochemist.com/ccimg/61000/60984-63-6.png)
![6A-[(2-aminoethyl)amino]-6A-deoxy- beta-Cyclodextrin](http://img.cochemist.com/ccimg/61000/60984-63-6_b.png)
