Displaying publications 21 - 40 of 355 in total

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  1. Cell-Free Expression of a Plant Membrane Protein BrPT2 From Boesenbergia Rotunda
    Liew YJM, Lee YK, Khalid N, Rahman NA, Tan BC
    Mol Biotechnol, 2021 Apr;63(4):316-326.
    PMID: 33565047 DOI: 10.1007/s12033-021-00304-z
    Prenylation of aromatic natural products by membrane-bound prenyltransferases (PTs) is an important biosynthesis step of many bioactive compounds. At present, only a few plant flavonoid-related PT genes have been functionally characterized, mainly due to the difficulties of expressing these membrane proteins. Rapid and effective methods to produce functional plant membrane proteins are thus indispensable. Here, we evaluated expression systems through cell-based and cell-free approaches to express Boesenbergia rotunda BrPT2 encoding a membrane-bound prenyltransferase. We attempted to express BrPT2 in Escherichia coli and tobacco plants but failed to detect this protein using the Western-blot technique, whereas an intact single band of 43 kDa was detected when BrPT2 was expressed using a cell-free protein synthesis system (PURE). Under in vitro enzymatic condition, the synthesized BrPT2 successfully catalyzed pinostrobin chalcone to pinostrobin. Molecular docking analysis showed that pinostrobin chalcone interacts with BrPT2 at two cavities: (1) the main binding site at the central cavity and (2) the allosteric binding site located away from the central cavity. Our findings suggest that cell-free protein synthesis could be an alternative for rapid production of valuable difficult-to-express membrane proteins.
    Matched MeSH terms: Models, Molecular
  2. Fulltext The structure of a major surface antigen SAG19 from Eimeria tenella unifies the Eimeria SAG family
    Ramly NZ, Dix SR, Ruzheinikov SN, Sedelnikova SE, Baker PJ, Chow YP, et al.
    Commun Biol, 2021 03 19;4(1):376.
    PMID: 33742128 DOI: 10.1038/s42003-021-01904-w
    In infections by apicomplexan parasites including Plasmodium, Toxoplasma gondii, and Eimeria, host interactions are mediated by proteins including families of membrane-anchored cysteine-rich surface antigens (SAGs) and SAG-related sequences (SRS). Eimeria tenella causes caecal coccidiosis in chickens and has a SAG family with over 80 members making up 1% of the proteome. We have solved the structure of a representative E. tenella SAG, EtSAG19, revealing that, despite a low level of sequence similarity, the entire Eimeria SAG family is unified by its three-layer αβα fold which is related to that of the CAP superfamily. Furthermore, sequence comparisons show that the Eimeria SAG fold is conserved in surface antigens of the human coccidial parasite Cyclospora cayetanensis but this fold is unrelated to that of the SAGs/SRS proteins expressed in other apicomplexans including Plasmodium species and the cyst-forming coccidia Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti. However, despite having very different structures, Consurf analysis showed that Eimeria SAG and Toxoplasma SRS families each exhibit marked hotspots of sequence hypervariability that map to their surfaces distal to the membrane anchor. This suggests that the primary and convergent purpose of the different structures is to provide a platform onto which sequence variability can be imposed.
    Matched MeSH terms: Models, Molecular
  3. Fulltext FKBP22 from the psychrophilic bacterium Shewanella sp. SIB1 selectively binds to the reduced state of insulin to prevent its aggregation
    Budiman C, Goh CKW, Arief II, Yusuf M
    Cell Stress Chaperones, 2021 Mar;26(2):377-386.
    PMID: 33247372 DOI: 10.1007/s12192-020-01183-0
    FKBP22 of a psychrophilic bacterium, Shewanella sp. SIB1 (SIB1 FKBP22), is a member of peptidyl-prolyl cis-trans isomerase (PPIase) and consists of N- and C-domains responsible for chaperone-like and PPIase catalytic activities, respectively. The chaperone-like activity of SIB1 FKBP22 was previously evidenced by its ability to prevent dithiothreitol (DTT)-induced insulin aggregation. Nevertheless, the mechanism by which this protein inhibits the aggregation remains unclear. To address this, the binding affinity of SIB1 FKBP22 to the native or reduced states of insulin was examined using surface plasmon resonance (SPR). The native and reduced states refer to insulin in the absence or DTT presence, respectively. The SPR sensorgram showed that SIB1 FKBP22 binds specifically to the reduced state of insulin, with a KD value of 37.31 ± 3.20 μM. This binding was facilitated by the N-domain, as indicated by the comparable KD values of the N-domain and SIB1 FKBP22. Meanwhile, the reduced state of insulin was found to have no affinity towards the C-domain. The KD value of SIB1 FKBP22 was slightly decreased by NaCl but was not severely affected by FK506, a specific FKBP inhibitor. Similarly, the prevention of DTT-induced aggregation by SIB1 FKBP22 was also modulated by the N-domain and was not affected by FK506. Further, the reduced and native states of insulin had no effect on the catalytic efficiency (kcat/KM) of SIB1 FKBP22 towards a peptide substrate. Nevertheless, the reduced state of insulin slightly reduced the catalytic efficiency towards refolding RNase T1, at up to 1.5-fold lower than in the absence of insulin. These results suggested that the binding event was mainly facilitated by hydrophobic interaction and was independent from its PPIase activity. Altogether, a possible mechanism by which SIB1 FKBP22 prevents DTT-induced insulin aggregation was proposed.
    Matched MeSH terms: Models, Molecular
  4. Fulltext Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
    den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, et al.
    Am J Hum Genet, 2021 02 04;108(2):346-356.
    PMID: 33513338 DOI: 10.1016/j.ajhg.2021.01.007
    Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
    Matched MeSH terms: Models, Molecular
  5. Fulltext Broad specificity of immune helminth scFv library to identify monoclonal antibodies targeting Strongyloides
    Rahumatullah A, Balachandra D, Noordin R, Baharudeen Z, Lim YY, Choong YS, et al.
    Sci Rep, 2021 01 28;11(1):2502.
    PMID: 33510342 DOI: 10.1038/s41598-021-82125-3
    Antibodies have different chemical properties capable of targeting a diverse nature of antigens. Traditionally, immune antibody libraries are perceived to be disease-specific with a skewed repertoire. The complexity during the generation of a combinatorial antibody library allows for a skewed but diverse repertoire to be generated. Strongyloides stercoralis is a parasite that causes strongyloidiasis, a potentially life-threatening disease with a complex diagnosis that impedes effective control and treatment of the disease. This study describes the isolation of monoclonal antibodies against S. stercoralis NIE recombinant protein using an immune antibody phage display library derived from lymphatic filaria-infected individuals. The isolated antibody clones showed both lambda and kappa light chains gene usage, with diverse amino acid distributions. Structural analysis showed that electropositivity and the interface area could determine the binding affinity of the clones with NIE. The successful identification of S. stercoralis antibodies from the filarial immune library highlights the breadth of antibody gene diversification in an immune antibody library that can be applied for closely related infections.
    Matched MeSH terms: Models, Molecular
  6. Proline-Modified UIO-66 as Nanocarriers to Enhance Candida rugosa Lipase Catalytic Activity and Stability for Electrochemical Detection of Nitrofen
    Cheng Y, Lai OM, Tan CP, Panpipat W, Cheong LZ, Shen C
    ACS Appl Mater Interfaces, 2021 Jan 27;13(3):4146-4155.
    PMID: 33440928 DOI: 10.1021/acsami.0c17134
    Immobilization can be used to improve the stability of lipases and enhances lipase recovery and reusability, which increases its commercial value and industrial applications. Nevertheless, immobilization frequently causes conformational changes of the lipases, which decrease lipase catalytic activity. in the present work, we synthesized UIO-66 and grafted UIO-66 crystals with proline for immobilization of Candida rugosa lipase (CRL). As indicated by steady-state fluorescence microscopy, grafting of proline onto UIO-66 crystals induced beneficial conformational change in CRL. CRL immobilized on UIO-66/Pro (CRL@UIO-66/Pro) demonstrated higher enzyme activity and better recyclability than that immobilized on UIO-66 (CRL@UIO-66) in both hydrolysis (CRL@UIO-66/Pro: 0.34 U; CRL@UIO-66: 0.15 U) and transesterification (CRL@UIO-66/Pro: 0.93 U; CRL@UIO-66: 0.25 U) reactions. The higher values of kcat and kcat/Km of CRL@UIO-66/Pro also showed that it had better catalytic efficiency as compared to CRL@UIO-66. It is also worth noting that CRL@UIO-66/Pro (0.93 U) demonstrated a much higher transesterification activity as compared to free CRL (0.11 U), indicating that UIO-66/Pro has increased the solvent stability of CRL. Both CRL@UIO-66 and CRL@UIO-66/Pro were also used for the fabrication of biosensors for nitrofen with a wide linear range (0-100 μM), lower limit of detection, and good recovery rate.
    Matched MeSH terms: Models, Molecular
  7. Fulltext Identification of novel human USP2 inhibitor and its putative role in treatment of COVID-19 by inhibiting SARS-CoV-2 papain-like (PLpro) protease
    Mirza MU, Ahmad S, Abdullah I, Froeyen M
    Comput Biol Chem, 2020 Dec;89:107376.
    PMID: 32979815 DOI: 10.1016/j.compbiolchem.2020.107376
    Human ubiquitin carboxyl-terminal hydrolase-2 (USP2) inhibitors, such as thiopurine analogs, have been reported to inhibit SARS-CoV papain-like proteases (PLpro). The PLpro have significant functional implications in the innate immune response during SARS-CoV-2 infection and considered an important antiviral target. Both proteases share strikingly similar USP fold with right-handed thumb-palm-fingers structural scaffold and conserved catalytic triad Cys-His-Asp/Asn. In this urgency situation of COVID-19 outbreak, there is a lack of in-vitro facilities readily available to test SARS-CoV-2 inhibitors in whole-cell assays. Therefore, we adopted an alternate route to identify potential USP2 inhibitor through integrated in-silico efforts. After an extensive virtual screening protocol, the best compounds were selected and tested. The compound Z93 showed significant IC50 value against Jurkat (9.67 μM) and MOTL-4 cells (11.8 μM). The binding mode of Z93 was extensively analyzed through molecular docking, followed by MD simulations, and molecular interactions were compared with SARS-CoV-2. The relative binding poses of Z93 fitted well in the binding site of both proteases and showed consensus π-π stacking and H-bond interactions with histidine and aspartate/asparagine residues of the catalytic triad. These results led us to speculate that compound Z93 might be the first potential chemical lead against SARS-CoV-2 PLpro, which warrants in-vitro evaluations.
    Matched MeSH terms: Models, Molecular
  8. Fulltext Pharmacophore modelling of vanillin derivatives, favipiravir, chloroquine, hydroxychloroquine, monolaurin and tetrodotoxin as MPro inhibitors of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)
    Law WY, Asaruddin MR, Bhawani SA, Mohamad S
    BMC Res Notes, 2020 Nov 11;13(1):527.
    PMID: 33176880 DOI: 10.1186/s13104-020-05379-6
    OBJECTIVES: The aim of this study was to use Ligand-based pharmacophore modelling approach for four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine for COVID-19 inhibitors as training sets. In this study Twenty vanillin derivatives together with monolaurin and tetrodotoxin were used as test sets to evaluate as potential SARS-CoV-2 inhibitors. The Structure-based pharmacophore modelling approach was also performed using 5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand-protein complex interactions.

    RESULTS: The pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition.

    Matched MeSH terms: Models, Molecular
  9. Fulltext Demystifying the catalytic pathway of Mycobacterium tuberculosis isocitrate lyase
    Ibeji CU, Salleh NAM, Sum JS, Ch'ng ACW, Lim TS, Choong YS
    Sci Rep, 2020 11 03;10(1):18925.
    PMID: 33144641 DOI: 10.1038/s41598-020-75799-8
    Pulmonary tuberculosis, caused by Mycobacterium tuberculosis, is one of the most persistent diseases leading to death in humans. As one of the key targets during the latent/dormant stage of M. tuberculosis, isocitrate lyase (ICL) has been a subject of interest for new tuberculosis therapeutics. In this work, the cleavage of the isocitrate by M. tuberculosis ICL was studied using quantum mechanics/molecular mechanics method at M06-2X/6-31+G(d,p): AMBER level of theory. The electronic embedding approach was applied to provide a better depiction of electrostatic interactions between MM and QM regions. Two possible pathways (pathway I that involves Asp108 and pathway II that involves Glu182) that could lead to the metabolism of isocitrate was studied in this study. The results suggested that the core residues involved in isocitrate catalytic cleavage mechanism are Asp108, Cys191 and Arg228. A water molecule bonded to Mg2+ acts as the catalytic base for the deprotonation of isocitrate C(2)-OH group, while Cys191 acts as the catalytic acid. Our observation suggests that the shuttle proton from isocitrate hydroxyl group C(2) atom is favourably transferred to Asp108 instead of Glu182 with a lower activation energy of 6.2 kcal/mol. Natural bond analysis also demonstrated that pathway I involving the transfer of proton to Asp108 has a higher intermolecular interaction and charge transfer that were associated with higher stabilization energy. The QM/MM transition state stepwise catalytic mechanism of ICL agrees with the in vitro enzymatic assay whereby Asp108Ala and Cys191Ser ICL mutants lost their isocitrate cleavage activities.
    Matched MeSH terms: Models, Molecular
  10. Functional characterisation and product specificity of Endo-β-1,3-glucanase from alkalophilic bacterium, Bacillus lehensis G1
    Jaafar NR, Khoiri NM, Ismail NF, Mahmood NAN, Abdul Murad AM, Abu Bakar FD, et al.
    Enzyme Microb Technol, 2020 Oct;140:109625.
    PMID: 32912685 DOI: 10.1016/j.enzmictec.2020.109625
    Endo-β-1,3-glucanase from alkalophilic bacterium, Bacillus lehensis G1 (Blg32) composed of 284 amino acids with a predicted molecular mass of 31.6 kDa is expressed in Escherichia coli and purified to homogeneity. Herein, Blg32 characteristics, substrates and product specificity as well as structural traits that might be involved in the production of sugar molecules are analysed. This enzyme functions optimally at the temperature of 70 °C, pH value of 8.0 with its catalytic activity strongly enhanced by Mn2+. Remarkably, the purified enzyme is highly stable in high temperature and alkaline conditions. It exhibits the highest activity on laminarin (376.73 U/mg) followed by curdlan and yeast β-glucan. Blg32 activity increased by 62% towards soluble substrate (laminarin) compared to insoluble substrate (curdlan). Hydrolytic products of laminarin were oligosaccharides with degree of polymerisation (DP) of 1 to 5 with the main product being laminaritriose (DP3). This suggests that the active site of Blg32 could recognise up to five glucose units. High concentration of Blg32 mainly produces glucose whilst low concentration of Blg32 yields oligosaccharides with different DP (predominantly DP3). A theoretical structural model of Blg32 was constructed and structural analysis revealed that Trp156 is involved in multiple hydrophobic stacking interactions. The amino acid was predicted to participate in substrate recognition and binding. It was also exhibited that catalytic groove of Blg32 has a narrow angle, thus limiting the substrate binding reaction. All these properties and knowledge of the subsites are suggested to be related to the possible mode of action of how Blg32 produces glucooligosaccharides.
    Matched MeSH terms: Models, Molecular
  11. In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein
    Quah SY, Tan MS, Ho KL, Manan NA, Gorfe AA, Deb PK, et al.
    Future Med Chem, 2020 09;12(18):1611-1631.
    PMID: 32892640 DOI: 10.4155/fmc-2020-0104
    Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
    Matched MeSH terms: Models, Molecular
  12. Fulltext Natural Flavonoids as Potential Angiotensin-Converting Enzyme 2 Inhibitors for Anti-SARS-CoV-2
    Muchtaridi M, Fauzi M, Khairul Ikram NK, Mohd Gazzali A, Wahab HA
    Molecules, 2020 Sep 01;25(17).
    PMID: 32882868 DOI: 10.3390/molecules25173980
    Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.
    Matched MeSH terms: Models, Molecular
  13. Quantitative structure-activity relationship model for classifying the diverse series of antifungal agents using ratio weighted penalized logistic regression
    Alharthi AM, Lee MH, Algamal ZY, Al-Fakih AM
    SAR QSAR Environ Res, 2020 Aug;31(8):571-583.
    PMID: 32628042 DOI: 10.1080/1062936X.2020.1782467
    One of the most challenging issues when facing a Quantitative structure-activity relationship (QSAR) classification model is to deal with the descriptor selection. Penalized methods have been adapted and have gained popularity as a key for simultaneously performing descriptor selection and QSAR classification model estimation. However, penalized methods have drawbacks such as having biases and inconsistencies that make they lack the oracle properties. This paper proposes an adaptive penalized logistic regression (APLR) to overcome these drawbacks. This is done by employing a ratio (BWR) of the descriptors between-groups sum of squares (BSS) to the within-groups sum of squares (WSS) for each descriptor as a weight inside the L1-norm. The proposed method was applied to one dataset that consists of a diverse series of antimicrobial agents with their respective bioactivities against Candida albicans. By experimental study, it has been shown that the proposed method (APLR) was more efficient in the selection of descriptors and classification accuracy than the other competitive methods that could be used in developing QSAR classification models. Another dataset was also successfully experienced. Therefore, it can be concluded that the APLR method had significant impact on QSAR analysis and studies.
    Matched MeSH terms: Models, Molecular
  14. Fulltext Combining In Silico and In Vitro Studies to Evaluate the Acetylcholinesterase Inhibitory Profile of Different Accessions and the Biomarker Triterpenes of Centella asiatica
    Jusril NA, Muhamad Juhari ANN, Abu Bakar SI, Md Saad WM, Adenan MI
    Molecules, 2020 Jul 24;25(15).
    PMID: 32721993 DOI: 10.3390/molecules25153353
    Alzheimer's disease (AD) is a neurodegenerative disease and the most cause of dementia in elderly adults. Acetylcholinesterase (AChE) is an important beneficial target for AD to control cholinergic signaling deficit. Centella asiatica (CA) has proven to be rich with active ingredients for memory enhancement. In the present study, the chemical profiling of three accession extracts of CA namely SECA-K017, SECA-K018, and, SECA-K019 were performed using high-performance liquid chromatography (HPLC). Four biomarker triterpene compounds were detected in all CA accessions. Quantitative analysis reveals that madecassoside was the highest triterpene in all the CA accessions. The biomarker compounds and the ethanolic extracts of three accessions were investigated for their acetylcholinesterase (AChE) inhibitory activity using Ellman's spectrophotometer method. The inhibitory activity of the triterpenes and accession extracts was compared with the standard AChE inhibitor eserine. The results from the in vitro study showed that the triterpene compounds exhibited an AChE inhibitory activity with the half-maximal inhibitory concentration (IC50) values between 15.05 ± 0.05 and 59.13 ± 0.18 µg/mL. Asiatic acid was found to possess strong AChE inhibitory activity followed by madecassic acid. Among the CA accession extracts, SECA-K017 and SECA-K018 demonstrated a moderate AChE inhibitory activity with an IC50 value of 481.5 ± 0.13 and 763.5 ± 0.16 µg/mL, respectively from the in silico docking studies, it is observed that asiatic acid and madecassic acid showed very good interactions with the active sites and fulfilled docking parameters against AChE. The present study suggested that asiatic acid and madecassic acid in the CA accessions could be responsible for the AChE inhibitory action and could be used as markers to guide further studies on CA as potential natural products for the treatment of AD.
    Matched MeSH terms: Models, Molecular
  15. Fulltext Modeling of Cu(II) Adsorption from an Aqueous Solution Using an Artificial Neural Network (ANN)
    Khan T, Binti Abd Manan TS, Isa MH, Ghanim AAJ, Beddu S, Jusoh H, et al.
    Molecules, 2020 Jul 17;25(14).
    PMID: 32708928 DOI: 10.3390/molecules25143263
    This research optimized the adsorption performance of rice husk char (RHC4) for copper (Cu(II)) from an aqueous solution. Various physicochemical analyses such as Fourier transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FESEM), carbon, hydrogen, nitrogen, and sulfur (CHNS) analysis, Brunauer-Emmett-Teller (BET) surface area analysis, bulk density (g/mL), ash content (%), pH, and pHZPC were performed to determine the characteristics of RHC4. The effects of operating variables such as the influences of aqueous pH, contact time, Cu(II) concentration, and doses of RHC4 on adsorption were studied. The maximum adsorption was achieved at 120 min of contact time, pH 6, and at 8 g/L of RHC4 dose. The prediction of percentage Cu(II) adsorption was investigated via an artificial neural network (ANN). The Fletcher-Reeves conjugate gradient backpropagation (BP) algorithm was the best fit among all of the tested algorithms (mean squared error (MSE) of 3.84 and R2 of 0.989). The pseudo-second-order kinetic model fitted well with the experimental data, thus indicating chemical adsorption. The intraparticle analysis showed that the adsorption process proceeded by boundary layer adsorption initially and by intraparticle diffusion at the later stage. The Langmuir and Freundlich isotherm models interpreted well the adsorption capacity and intensity. The thermodynamic parameters indicated that the adsorption of Cu(II) by RHC4 was spontaneous. The RHC4 adsorption capacity is comparable to other agricultural material-based adsorbents, making RHC4 competent for Cu(II) removal from wastewater.
    Matched MeSH terms: Models, Molecular
  16. Fulltext Structural Basis of Specific Glucoimidazole and Mannoimidazole Binding by Os3BGlu7
    Nutho B, Pengthaisong S, Tankrathok A, Lee VS, Ketudat Cairns JR, Rungrotmongkol T, et al.
    Biomolecules, 2020 Jun 15;10(6).
    PMID: 32549280 DOI: 10.3390/biom10060907
    β-Glucosidases and β-mannosidases hydrolyze substrates that differ only in the epimer of the nonreducing terminal sugar moiety, but most such enzymes show a strong preference for one activity or the other. Rice Os3BGlu7 and Os7BGlu26 β-glycosidases show a less strong preference, but Os3BGlu7 and Os7BGlu26 prefer glucosides and mannosides, respectively. Previous studies of crystal structures with glucoimidazole (GIm) and mannoimidazole (MIm) complexes and metadynamic simulations suggested that Os7BGlu26 hydrolyzes mannosides via the B2,5 transition state (TS) conformation preferred for mannosides and glucosides via their preferred 4H3/4E TS conformation. However, MIm is weakly bound by both enzymes. In the present study, we found that MIm was not bound in the active site of crystallized Os3BGlu7, but GIm was tightly bound in the -1 subsite in a 4H3/4E conformation via hydrogen bonds with the surrounding residues. One-microsecond molecular dynamics simulations showed that GIm was stably bound in the Os3BGlu7 active site and the glycone-binding site with little distortion. In contrast, MIm initialized in the B2,5 conformation rapidly relaxed to a E3/4H3 conformation and moved out into a position in the entrance of the active site, where it bound more stably despite making fewer interactions. The lack of MIm binding in the glycone site in protein crystals and simulations implies that the energy required to distort MIm to the B2,5 conformation for optimal active site residue interactions is sufficient to offset the energy of those interactions in Os3BGlu7. This balance between distortion and binding energy may also provide a rationale for glucosidase versus mannosidase specificity in plant β-glycosidases.
    Matched MeSH terms: Models, Molecular
  17. Fulltext Three-Component Access to Functionalized Spiropyrrolidine Heterocyclic Scaffolds and Their Cholinesterase Inhibitory Activity
    Boudriga S, Haddad S, Murugaiyah V, Askri M, Knorr M, Strohmann C, et al.
    Molecules, 2020 Apr 23;25(8).
    PMID: 32340203 DOI: 10.3390/molecules25081963
    A novel one-pot [3+2]-cycloaddition reaction of (E)-3-arylidene-1-phenyl-succinimides, cyclic 1,2-diketones (isatin, 5-chloro-isatin and acenaphtenequinone), and diverse α-aminoacids such as 2-phenylglycine or sarcosine is reported. The reaction provides succinimide-substituted dispiropyrrolidine derivatives with high regio- and diastereoselectivities under mild reaction conditions. The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies. Several synthetized compounds show higher inhibition on acetylcholinesterase (AChE) than butyrylcholinesterase (BChE). Of the 17 synthesized compounds tested, five exhibit good AChE inhibition with IC50 of 11.42 to 22.21 µM. A molecular docking study has also been undertaken for compound 4n possessing the most potent AChE inhibitory activity, disclosing its binding to the peripheral anionic site of AChE enzymes.
    Matched MeSH terms: Models, Molecular
  18. Fulltext Structure-Based Design of Antivirals against Envelope Glycoprotein of Dengue Virus
    Anasir MI, Ramanathan B, Poh CL
    Viruses, 2020 03 26;12(4).
    PMID: 32225021 DOI: 10.3390/v12040367
    Dengue virus (DENV) presents a significant threat to global public health with more than 500,000 hospitalizations and 25,000 deaths annually. Currently, there is no clinically approved antiviral drug to treat DENV infection. The envelope (E) glycoprotein of DENV is a promising target for drug discovery as the E protein is important for viral attachment and fusion. Understanding the structure and function of DENV E protein has led to the exploration of structure-based drug discovery of antiviral compounds and peptides against DENV infections. This review summarizes the structural information of the DENV E protein with regards to DENV attachment and fusion. The information enables the development of antiviral agents through structure-based approaches. In addition, this review compares the potency of antivirals targeting the E protein with the antivirals targeting DENV multifunctional enzymes, repurposed drugs and clinically approved antiviral drugs. None of the current DENV antiviral candidates possess potency similar to the approved antiviral drugs which indicates that more efforts and resources must be invested before an effective DENV drug materializes.
    Matched MeSH terms: Models, Molecular
  19. Dual platform based sandwich assay surface-enhanced Raman scattering DNA biosensor for the sensitive detection of food adulteration
    Khalil I, Yehye WA, Muhd Julkapli N, Sina AA, Rahmati S, Basirun WJ, et al.
    Analyst, 2020 Feb 17;145(4):1414-1426.
    PMID: 31845928 DOI: 10.1039/c9an02106j
    Surface enhanced Raman scattering (SERS) DNA biosensing is an ultrasensitive, selective, and rapid detection technique with the ability to produce molecule-specific distinct fingerprint spectra. It supersedes the long amplicon based PCR assays, the fluorescence and spectroscopic techniques with their quenching and narrow spectral bandwidth, and the electrochemical detection techniques using multiplexing. However, the performance of the SERS DNA biosensor relies on the DNA probe length, platform composition, both the presence and position of Raman tags and the chosen sensing strategy. In this context, we herein report a SERS biosensor based on dual nanoplatforms with a uniquely designed Raman tag (ATTO Rho6G) intercalated short-length DNA probe for the sensitive detection of the pig species Sus scrofa. In the design of the signal probe (SP), a Raman tag was incorporated adjacent to the spacer arm, followed by a terminal thiol modifier, which consequently had a strong influence on the SERS signal enhancement. The detection strategy involves the probe-target DNA hybridization mediated coupling of the two platforms, i.e., the graphene oxide-gold nanorod (GO-AuNR) functionalized capture probe (CP) and SP-conjugated gold nanoparticles (AuNPs), consequently enhancing the SERS intensity by both the electromagnetic hot spots generated at the junctions or interstices of the two platforms and the chemical enhancement between the AuNPs and the adsorbed intercalated Raman tag. This dual platform based SERS DNA biosensor exhibited outstanding sensitivity in detecting pork DNA with a limit of detection (LOD) of 100 aM validated with DNA extracted from a pork sample (LOD 1 fM). Moreover, the fabricated SERS biosensor showed outstanding selectivity and specificity for differentiating the DNA sequences of six closely related non-target species from the target DNA sequences with single and three nucleotide base-mismatches. Therefore, the developed short-length DNA linked dual platform based SERS biosensor could replace the less sensitive traditional methods of pork DNA detection and be adopted as a universal detection approach for the qualitative and quantitative detection of DNA from any source.
    Matched MeSH terms: Models, Molecular
  20. Fulltext Investigation of α-Glucosidase Inhibitory Metabolites from Tetracera scandens Leaves by GC-MS Metabolite Profiling and Docking Studies
    Nokhala A, Siddiqui MJ, Ahmed QU, Ahamad Bustamam MS, Zakaria AZA
    Biomolecules, 2020 02 12;10(2).
    PMID: 32059529 DOI: 10.3390/biom10020287
    Stone leaf (Tetracera scandens) is a Southeast Asian medicinal plant that has been traditionally used for the management of diabetes mellitus. The underlying mechanisms of the antidiabetic activity have not been fully explored yet. Hence, this study aimed to evaluate the α-glucosidase inhibitory potential of the hydromethanolic extracts of T. scandens leaves and to characterize the metabolites responsible for such activity through gas chromatography-mass spectrometry (GC-MS) metabolomics. Crude hydromethanolic extracts of different strengths were prepared and in vitro assayed for α-glucosidase inhibition. GC-MS analysis was further carried out and the mass spectral data were correlated to the corresponding α-glucosidase inhibitory IC50 values via an orthogonal partial least squares (OPLS) model. The 100%, 80%, 60% and 40% methanol extracts displayed potent α-glucosidase inhibitory potentials. Moreover, the established model identified 16 metabolites to be responsible for the α-glucosidase inhibitory activity of T. scandens. The putative α-glucosidase inhibitory metabolites showed moderate to high affinities (binding energies of -5.9 to -9.8 kcal/mol) upon docking into the active site of Saccharomyces cerevisiae isomaltase. To sum up, an OPLS model was developed as a rapid method to characterize the α-glucosidase inhibitory metabolites existing in the hydromethanolic extracts of T. scandens leaves based on GC-MS metabolite profiling.
    Matched MeSH terms: Models, Molecular
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