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Computational docking, molecular dynamics simulation and subsite structure analysis of a maltogenic amylase from Bacillus lehensis G1 provide insights into substrate and product specificity

Manas NH, Bakar FD, Illias RM

J Mol Graph Model, 2016 06;67:1-13.
PMID: 27155296 DOI: 10.1016/j.jmgm.2016.04.004

Maltogenic amylase (MAG1) from Bacillus lehensis G1 displayed the highest hydrolysis activity on β-cyclodextrin (β-CD) to produce maltose as a main product and exhibited high transglycosylation activity on malto-oligosaccharides with polymerization degree of three and above. These substrate and product specificities of MAG1 were elucidated from structural point of view in this study. A three-dimensional structure of MAG1 was constructed using homology modeling. Docking of β-CD and malto-oligosaccharides was then performed in the MAG1 active site. An aromatic platform in the active site was identified which is responsible in substrate recognition especially in determining the enzyme's preference toward β-CD. Molecular dynamics (MD) simulation showed MAG1 structure is most stable when docked with β-CD and least stable when docked with maltose. The docking analysis and MD simulation showed that the main subsites for substrate stabilization in the active site are -2, -1, +1 and +2. A bulky residue, Trp359 at the +2 subsite was identified to cause steric interference to the bound linear malto-oligosaccharides thus prevented it to occupy subsite +3, which can only be reached by a highly bent glucose molecule such as β-CD. The resulted modes of binding from docking simulation show a good correlation with the experimentally determined hydrolysis pattern. The subsite structure generated from this study led to a possible mode of action that revealed how maltose was mainly produced during hydrolysis. Furthermore, maltose only occupies subsite +1 and +2, therefore could not be hydrolyzed or transglycosylated by the enzyme. This important knowledge has paved the way for a novel structure-based molecular design for modulation of its catalytic activities.

Matched MeSH terms: beta-Cyclodextrins/chemistry
Effect of Gum Arabic, β-Cyclodextrin, and Sodium Caseinate as Encapsulating Agent on the Oxidative Stability and Bioactive Compounds of Spray-Dried Kenaf Seed Oil

Chew SC, Tan CP, Nyam KL

J Food Sci, 2018 Sep;83(9):2288-2294.
PMID: 30074623 DOI: 10.1111/1750-3841.14291

Kenaf seed oil is prone to undergo oxidation due to its high content of unsaturated fatty acids, thus microencapsulation stands as an alternative to protect kenaf seed oil from the adverse environment. This study primarily aimed to evaluate the oxidative stability of microencapsulated refined kenaf seed oil (MRKSO) by the use of gum arabic, β-cyclodextrin, and sodium caseinate as the wall materials by spray drying. Bulk refined kenaf seed oil (BRKSO) and MRKSO were kept at 65 °C for 24 days to evaluate its oxidative stability, changes of tocopherol and tocotrienol contents, phytosterol content, and fatty acid profile. The results showed that the peroxide value, p-Anisidine value, and total oxidation value of BRKSO were significantly higher than the MRKSO at day 24. The total tocopherol and tocotrienol contents were reduced 66.1% and 56.8% in BRKSO and MRKSO, respectively, upon the storage. There was a reduction of 71.7% and 23.5% of phytosterol content in BRKSO and MRKSO, respectively, upon the storage. The degradation rate of polyunsaturated fatty acids in BRKSO was higher than that of MRKSO. This study showed that the current microencapsulation technique is a feasible way to retard the oxidation of kenaf seed oil.
PRACTICAL APPLICATION: There is increasing research on the functional properties of crude kenaf seed oil, but the crude kenaf seed oil is not edible. This study offered in developing of microencapsulated refined kenaf seed oil by spray drying, which is suitable for food application. The microencapsulation of refined kenaf seed oil with healthier wall materials is beneficial in developing a diversity of functional food products and supplements.

Matched MeSH terms: beta-Cyclodextrins*
Liquid chromatography-tandem mass spectroscopic method for the determination of zerumbone in human plasma and its application to pharmacokinetics

Eid EE, Abdul AB, Rasedee A, Suliman FE, Sukari MA, Fatah SA

J Mass Spectrom, 2011 Aug;46(8):772-81.
PMID: 21834015 DOI: 10.1002/jms.1942

A rapid, sensitive, specific and selective LC-MS/MS method for the determination of zerumbone (ZER) in human plasma using 2,4-diamino-6-(4-methoxyphenyl)-1,3,5-triazine (DMTZ) as an internal standard (IS) has been developed and validated. ZER was chromatographed on C8 column using a mobile phase of acetonitrile/water (80:20, v/v) at a flow rate of 0.25 ml min(-1) . Quantitation was achieved using ESI+ interface, employing multiple reaction monitoring (MRM) mode at m/z 219 > 81 and 218 > 134 for ZER and IS, respectively. The calibration standards were linear over a range of 5-3000 ng ml(-1) (r(2)=0.9994) with an LLOQ of 5 ng ml(-1) (RSD %; 11.4% and bias%; 9.5%). Intra- and inter-day precision of ZER assay ranged from 0.18 to 3.56% with accuracy (bias) that varied between -5.09 and 4.3%, demonstrating good precision and accuracy. Recoveries of ZER and the IS from human plasma were above 85%. The developed method was validated for the determination of ZER in rat plasma. Linearity, stability of ZER and the ME on rat plasma were discussed. The applicability of the developed method was demonstrated by measuring ZER in rat plasma samples following intravenous and intraperitoneal administration of ZER prepared in hydroxypropyl-β-cyclodextrin (HPβCD) and sodium carboxymethyl cellulose (CMC), respectively, in 20 mg kg(-1) and this study indicated a clear significant difference (p<0.05) in pharmacokinetic parameters of ZER in ZER/HPβCD complex compared with ZER in CMC preparation.

Matched MeSH terms: beta-Cyclodextrins/chemistry
Molecular Modeling-Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells

Maki MAA, Kumar PV, Cheah SC, Siew Wei Y, Al-Nema M, Bayazeid O, et al.

ACS Omega, 2019 May 31;4(5):8767-8777.
PMID: 31459966 DOI: 10.1021/acsomega.9b00109

Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical trials. Combination therapy is one of the options that could increase the efficacy and decrease the toxicity of the anticancer therapy. This study revealed that the β-cyclodextrin (β-CD):FGF7 complex has the potential to improve the antiproliferative effect of EV by preventing FGF receptor activation and by enhancing EV cellular uptake and intracellular retention. Molecular docking techniques were used to investigate the possible interaction between EV, β-CD, and FGF7. Molecular docking insights revealed that β-CD and EV are capable to form a stable inclusion complex with FGF at the molecular level. The aqueous solubility of the inclusion complex was increased (3.1 ± 0.23 μM) when compared to the aqueous solubility of pure EV (1.7 ± 0.16 μM). In addition, the in vitro cytotoxic activity of a FGF7:β-CD:EV complex on Caco-2 cell line was investigated using real-time xCELLigence technology. The FGF7:β-CD:EV complex has induced apoptosis of Caco-2 cells and shown higher cytotoxic activity than the parent drug EV. With the multitargets effect of β-CD:FGF7 and EV, the antiproliferative effect of EV was remarkably improved as the IC50 value of EV was reduced from 9.65 ± 1.42 to 1.87 ± 0.33 μM when compared to FGF7:β-CD:EV complex activity. In conclusion, the findings advance the understanding of the biological combinational effects of the β-CD:FGF7 complex and EV as an effective treatment to combat CRC.

Matched MeSH terms: beta-Cyclodextrins
Inducing G2/M Cell Cycle Arrest and Apoptosis through Generation Reactive Oxygen Species (ROS)-Mediated Mitochondria Pathway in HT-29 Cells by Dentatin (DEN) and Dentatin Incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD)

Ashwaq AS, Al-Qubaisi MS, Rasedee A, Abdul AB, Taufiq-Yap YH, Yeap SK

Int J Mol Sci, 2016 Oct 18;17(10).
PMID: 27763535

Dentatin (DEN), purified from the roots of Clausena excavata Burm f., has poor aqueous solubility that reduces its therapeutic application. The aim of this study was to assess the effects of DEN-HPβCD (hydroxypropyl-β-cyclodextrin) complex as an anticancer agent in HT29 cancer cell line and compare with a crystal DEN in dimethyl sulfoxide (DMSO). The exposure of the cancer cells to DEN or DEN-HPβCD complex leads to cell growth inhibition as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. To analyze the mechanism, in which DEN or DEN-HPβCD complex causes the death in human colon HT29 cancer cells, was evaluated by the enzyme-linked immunosorbent assay (ELIZA)-based assays for caspase-3, 8, 9, and reactive oxygen species (ROS). The findings showed that an anti-proliferative effect of DEN or DEN-HPβCD complex were via cell cycle arrest at the G2/M phase and eventually induced apoptosis through both mitochondrial and extrinsic pathways. The down-regulation of poly(ADP-ribose) polymerase (PARP) which leaded to apoptosis upon treatment, was investigated by Western-blotting. Hence, complexation between DEN and HPβCD did not diminish or eliminate the effective properties of DEN as anticancer agent. Therefore, it would be possible to resolve the conventional and current issues associated with the development and commercialization of antineoplastic agents in the future.

Matched MeSH terms: beta-Cyclodextrins/chemistry