Displaying publications 1 - 20 of 88 in total

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  1. Fragment-based molecular design of new competitive dengue Den2 Ns2b/Ns3 inhibitors from the components of fingerroot (Boesenbergia rotunda)
    Frimayanti N, Zain SM, Lee VS, Wahab HA, Yusof R, Abd Rahman N
    In Silico Biol. (Gedrukt), 2011;11(1-2):29-37.
    PMID: 22475750 DOI: 10.3233/ISB-2012-0442
    Publication year=2011-2012
  2. Diaminobenzene schiff base, a novel class of DNA minor groove binder
    Helal MH, Al-Mudaris ZA, Al-Douh MH, Osman H, Wahab HA, Alnajjar BO, et al.
    Int J Oncol, 2012 Aug;41(2):504-10.
    PMID: 22614449 DOI: 10.3892/ijo.2012.1491
    Molecules that target the deoxyribonucleic acid (DNA) minor groove are relatively sequence specific and they can be excellent carrier structures for cytotoxic chemotherapeutic compounds which can help to minimize side effects. Two novel isomeric derivatives of diaminobenzene Schiff base [N,N'-bis (2-hydroxy-3-methoxybenzylidene)-1,2-diaminobenzene (2MJ) and N,N'-bis(2-hydroxy-3-methoxybenzylidene)-1,3-diaminobenzene (2MH)] were analyzed for their DNA minor groove binding (MGB) ability using viscometry, UV and fluorescence spectroscopy, computational modeling and clonogenic assay. The result shows that 2MJ and 2MH are strong DNA MGBs with the latter being more potent. 2MH can form interstrand hydrogen bond linkages at its oxygens with N3 of adenines. Changing the 2-hydroxy-3-methoxybenzylidene binding position to the 1,3 location on the diaminobenzene structure (2MJ) completely removed any viable hydrogen bond formation with the DNA and caused significant decrease in binding strength and minor groove binding potency. Neither compound showed any significant cytotoxicity towards human breast, colon or liver cancer cell lines.
  3. tLyp-1: A peptide suitable to target NRP-1 receptor
    Larue L, Kenzhebayeva B, Al-Thiabat MG, Jouan-Hureaux V, Mohd-Gazzali A, Wahab HA, et al.
    Bioorg Chem, 2023 Jan;130:106200.
    PMID: 36332316 DOI: 10.1016/j.bioorg.2022.106200
    Targeting vascular endothelial growth factor receptor (VEFGR) and its co-receptor neuropilin-1 (NRP-1) is an interesting vascular strategy. tLyp-1 is a tumor-homing and penetrating peptide of 7 amino acids (CGNKRTR). It is a truncated form of Lyp-1 (CGNKRTRGC), which is known to target NRP-1 receptor, with high affinity and specificity. It is mediated by endocytosis via C-end rule (CendR) internalization pathway. The aim of this study is to evaluate the importance of each amino acid in the tLyp-1 sequence through alanine-scanning (Ala-scan) technique, during which each of the amino acid in the sequence was systematically replaced by alanine to produce 7 different analogues. In silico approach through molecular docking and molecular dynamics are employed to understand the interaction between the peptide and its analogues with the NRP-1 receptor, followed by in vitro ligand binding assay study. The C-terminal Arg is crucial in the interaction of tLyp-1 with NRP-1 receptor. Substituting this residue dramatically reduces the affinity of this peptide which is clearly seen in this study. Lys-4 is also important in the interaction, which is confirmed via the in vitro study and the MM-PBSA analysis. The finding in this study supports the CendR, in which the presence of R/K-XX-R/K motif is essential in the binding of a ligand with NRP-1 receptor. This presented work will serve as a guide in the future work pertaining the development of active targeting agent towards NRP-1 receptor.
  4. Development, optimization and characterization of cisplatin loaded cubosomes for human lung carcinoma
    Umar H, Wahab HA, Ahmed N, Fujimura NA, Amjad MW, Bukhari SNA, et al.
    Drug Dev Ind Pharm, 2024 Mar 20.
    PMID: 38451066 DOI: 10.1080/03639045.2024.2326043
    OBJECTIVES: This study aimed to develop, optimize and evaluate glyceryl monooleate (GMO) based cubosomes as a drug delivery system containing cisplatin for treatment of human lung carcinoma.

    SIGNIFICANCE: The significance of this research was to successfully incorporate slightly water soluble and potent anticancer drug (cisplatin) into cubosomes, which provide slow and sustained release of drug for longer period of time.

    METHODS: The delivery system was developed through top-down approach by melting GMO and poloxamer 407 (P407) at 70 °C and then drop-wise addition of warm deionized water (70 °C) containing cisplatin. The formulation then exposed to probe sonicator for about 2 min. A randomized regular two level full factorial design with help of Design Expert was used for optimization of blank cubosomal formulations. Cisplatin loaded cubosomes were then subjected to physico-chemical characterization.

    RESULTS: The characterization of the formulation revealed that it had a sufficient surface charge of -9.56 ± 1.33 mV, 168.25 ± 5.73 nm particle size, and 60.64 ± 0.11% encapsulation efficiency. The in vitro release of cisplatin from the cubosomes at pH 7.4 was observed to be sustained, with 94.5% of the drug being released in 30 h. In contrast, 99% of cisplatin was released from the drug solution in just 1.5 h. In vitro cytotoxicity assay was conducted on the human lung carcinoma NCI-H226 cell line, the cytotoxicity of cisplatin-loaded cubosomes was relative to that of pure cisplatin solution, while blank (without cisplatin) cubosomes were nontoxic.

    CONCLUSIONS: The obtained results demonstrated the successful development of cubosomes for sustained delivery of cisplatin.

  5. Platinum-based targeted chemotherapies and reversal of cisplatin resistance in non-small cell lung cancer (NSCLC)
    Umar H, Wahab HA, Attiq A, Amjad MW, Bukhari SNA, Ahmad W
    Mutat Res, 2024 Mar 19;828:111856.
    PMID: 38520879 DOI: 10.1016/j.mrfmmm.2024.111856
    Lung cancer is the one of the most prevalent cancer in the world. It kills more people from cancer than any other cause and is especially common in underdeveloped nations. With 1.2 million instances, it is also the most prevalent cancer in men worldwide, making about 16.7% of the total cancer burden. Surgery is the main form of curative treatment for early-stage lung cancer. However, the majority of patients had incurable advanced non-small cell lung cancer (NSCLC) recurrence after curative purpose surgery, which is indicative of the aggressiveness of the illness and the dismal outlook. The gold standard of treatment for NSCLC patients includes drug targeting of specific mutated genes drive in development of lung cancer. Furthermore, patients with advanced NSCLC and those with early-stage illness needing adjuvant therapy should use cisplatin as it is the more active platinum drug. So, this review encompasses the non-small cell lung cancer microenvironment, treatment approaches, and use of cisplatin as a first-line regimen for NSCLC, its mechanism of action, cisplatin resistance in NSCLC and also the prevention strategies to revert the drug resistance.
  6. Advancing Women in Chemistry
    Cournia Z, Soares TA, Wahab HA, Amaro RE
    J Chem Inf Model, 2021 11 22;61(11):5305-5306.
    PMID: 34668709 DOI: 10.1021/acs.jcim.1c01185
  7. Celebrating Diversity, Equity, Inclusion, and Respect in Computational and Theoretical Chemistry
    Cournia Z, Soares TA, Wahab HA, Amaro RE
    J Chem Inf Model, 2022 Dec 26;62(24):6287-6291.
    PMID: 36567670 DOI: 10.1021/acs.jcim.2c01543
  8. Fulltext The influence of leadership quality towards community cohesion in Iban community in Malaysia
    Rezaul Islam M, Wahab HA, Anggum LA
    Heliyon, 2020 Feb;6(2):e03370.
    PMID: 32072057 DOI: 10.1016/j.heliyon.2020.e03370
    This study aimed to examine the influence of the traditional leadership qualities towards to develop community cohesion in the Iban community in Malaysia. A quantitative approach was used to conduct this study, where data were collected through a self-administered survey questionnaire from 210 chiefs in the Iban longhouse at the Pakan District in Sarawak, Malaysia. A pre-tested questionaire was administrered to the respondents using a simple random sampling in the District of Pakan, Sarawak. The leadership quality was measured based on the leadership traits, leadership style, leadership behaviour, situational leadership, and trsnformational leadership; while the community cohesion was measured by a sense of belonging, social alienation, social support, rootedness, social solidarity, and social ties. The results of the correlation and regression analysis showed that the traditional leadership qualities had a significant correlation with the development of social cohesion. The findings proved that the traditional leadership is essential to increase community cohesion in the Iban community. The findings would be important guideline to the development thinkers, practitioners, community leaders, and development institutions.
  9. The protective effects of Zingiber zerumbet rhizome against fevers in rats
    Mohd Salleh H, Ablat A, Chong SL, Hazni H, Tohar N, Fauzi N, et al.
    Naturwissenschaften, 2024 Apr 01;111(2):20.
    PMID: 38558027 DOI: 10.1007/s00114-024-01907-7
    The Zingiber zerumbet rhizomes are traditionally used to treat fever, and the in vitro inhibitory effect of ethyl acetate extract from Zingiber zerumbet rhizomes (EAEZZR) against DENV2 NS2B/NS3 (two non-structural proteins, NS2 and NS3 of dengue virus type 2) has been reported earlier. This study was carried out to establish an acute toxicity profile and evaluate the anti-fever (anti-pyretic) activities of EAEZZR in yeast-induced fever in rats. The major compound of EAEZZR, zerumbone, was isolated using chromatographic methods including column chromatography (CC) and preparative thin-layer chromatography (PTLC). Additionally, the structure of zerumbone was elucidated using nuclear magnetic resonance (NMR), liquid chromatography mass spectrometer-ion trap-time of flight (LCMS-IT-TOF), infrared (IR), and ultraviolet (UV) spectroscopy. The toxicity of EAEZZR was evaluated using Organization for Economic Cooperation and Development Test Guideline 425 (OECD tg-425) with minor modifications at concentrations EAEZZR of 2000 mg/kg, 3000 mg/kg, and 5000 mg/kg. Anti-fever effect was determined by yeast-induced fever (pyrexia) in rats. The acute toxicity study showed that EAEZZR is safe at the highest 5000 mg/kg body weight dose in Sprague Dawley rats. Rats treated with EAEZZR at doses of 125, 250, and 500 mg/kg exhibited a significant reduction in rectal temperature (TR) in the first 1 h. EAEZZR at the lower dose of 125 mg/kg showed substantial potency against yeast-induced fever for up to 2 h compared to 0 h in controls. A significant reduction of TR was observed in rats treated with standard drug aspirin in the third through fourth hours. Based on the present findings, ethyl acetate extract of Zingiber zerumbet rhizomes could be considered safe up to the dose of 5000 mg/kg, and the identification of active ingredients of Zingiber zerumbet rhizomes may allow their use in the treatment of fever with dengue virus infection.
  10. Fulltext Synthesis, biological activities, and evaluation molecular docking-dynamics studies of new phenylisoxazole quinoxalin-2-amine hybrids as potential α-amylase and α-glucosidase inhibitors
    Mohd Radzuan SN, Phongphane L, Abu Bakar MH, Che Omar MT, Nor Shahril NS, Supratman U, et al.
    RSC Adv, 2024 Feb 29;14(11):7684-7698.
    PMID: 38444963 DOI: 10.1039/d3ra08642a
    New phenylisoxazole quinoxalin-2-amine hybrids 5a-i were successfully synthesised with yields of 53-85% and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro α-amylase and α-glucosidase inhibitory assays, with acarbose as the positive control. Through the biological study, compound 5h exhibits the highest α-amylase inhibitory activity with IC50 = 16.4 ± 0.1 μM while compounds 5a-c, 5e and 5h exhibit great potential as α-glucosidase inhibitors, with 5c being the most potent (IC50 = 15.2 ± 0.3 μM). Among the compounds, 5h exhibits potential as a dual inhibitor for both α-amylase (IC50 = 16.4 ± 0.1 μM) and α-glucosidase (IC50 = 31.6 ± 0.4 μM) enzymes. Through the molecular docking studies, the inhibition potential of the selected compounds is supported. Compound 5h showed important interactions with α-amylase enzyme active sites and exhibited the highest binding energy of -8.9 ± 0.10 kcal mol-1, while compound 5c exhibited the highest binding energy of -9.0 ± 0.20 kcal mol-1 by forming important interactions with the α-glucosidase enzyme active sites. The molecular dynamics study showed that the selected compounds exhibited relative stability when binding with α-amylase and α-glucosidase enzymes. Additionally, compound 5h demonstrated a similar pattern of motion and mechanism of action as the commercially available miglitol.
  11. Fulltext Multi-population Black Hole Algorithm for the problem of data clustering
    Salih SQ, Alsewari AA, Wahab HA, Mohammed MKA, Rashid TA, Das D, et al.
    PLoS One, 2023;18(7):e0288044.
    PMID: 37406006 DOI: 10.1371/journal.pone.0288044
    The retrieval of important information from a dataset requires applying a special data mining technique known as data clustering (DC). DC classifies similar objects into a groups of similar characteristics. Clustering involves grouping the data around k-cluster centres that typically are selected randomly. Recently, the issues behind DC have called for a search for an alternative solution. Recently, a nature-based optimization algorithm named Black Hole Algorithm (BHA) was developed to address the several well-known optimization problems. The BHA is a metaheuristic (population-based) that mimics the event around the natural phenomena of black holes, whereby an individual star represents the potential solutions revolving around the solution space. The original BHA algorithm showed better performance compared to other algorithms when applied to a benchmark dataset, despite its poor exploration capability. Hence, this paper presents a multi-population version of BHA as a generalization of the BHA called MBHA wherein the performance of the algorithm is not dependent on the best-found solution but a set of generated best solutions. The method formulated was subjected to testing using a set of nine widespread and popular benchmark test functions. The ensuing experimental outcomes indicated the highly precise results generated by the method compared to BHA and comparable algorithms in the study, as well as excellent robustness. Furthermore, the proposed MBHA achieved a high rate of convergence on six real datasets (collected from the UCL machine learning lab), making it suitable for DC problems. Lastly, the evaluations conclusively indicated the appropriateness of the proposed algorithm to resolve DC issues.
  12. Synthesis and discovery of novel piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent cholinesterase inhibitors
    Kia Y, Osman H, Kumar RS, Murugaiyah V, Basiri A, Perumal S, et al.
    Bioorg Med Chem, 2013 Apr 1;21(7):1696-707.
    PMID: 23454132 DOI: 10.1016/j.bmc.2013.01.066
    Three-component reaction of a series of 1-acryloyl-3,5-bisbenzylidenepiperidin-4-ones with isatin and L-proline in 1:1:1 and 1:2:2 molar ratios in methanol afforded, respectively the piperidone-grafted novel mono- and bisspiro heterocyclic hybrids comprising functionalized piperidine, pyrrolizine and oxindole ring systems in good yields. The in vitro evaluation of cholinesterase enzymes inhibitory activity of these cycloadducts disclosed that monospiripyrrolizines (8a-k), are more active with IC50 ranging from 3.36 to 20.07 μM than either the dipolarophiles (5a-k) or bisspiropyrrolizines (9a-k). The compounds, 8i and 8e with IC50 values of 3.36 and 3.50 μM, respectively showed the maximum inhibition of acethylcholinesterase (AChE) and butrylylcholinestrase (BuChE). Molecular modeling simulation, disclosed the binding interactions of the most active compounds to the active site residues of their respective enzymes. The docking results were in accordance with the IC50 values obtained from in vitro cholinesterase assay.
  13. Breaking barriers: bilosomes gel potentials to pave the way for transdermal breast cancer treatment with Tamoxifen
    Abou Assi R, Abdulbaqi IM, Tan SM, Wahab HA, Darwis Y, Chan SY
    Drug Dev Ind Pharm, 2023 Sep 18.
    PMID: 37722711 DOI: 10.1080/03639045.2023.2256404
    OBJECTIVE: Breast cancer affects women globally, regardless of age or location. On the other hand, Tamoxifen (TXN), a class II biopharmaceutical drug is acting as a prophylactic/treating agent for women at risk of and/or with hormone receptor-positive breast cancer. However, its oral administration has life-threatening side effects, which have led researchers to investigate alternative delivery methods. One such method is transdermal drug delivery utilizing bile salts as penetration enhancers, aka Bilosomes.

    METHODS: Bilosomes formulations were optimized statistically for the outcome of vesicle shape, size, and entrapment efficiency using two types of bile, i.e. sodium taurocholate and sodium cholate. These bilosomes were then loaded into HPMC base gel and further characterized for their morphology, drug content, pH, viscosity, spreadability and eventually ex-vivo skin penetration and deposition studies.

    RESULTS: Findings showed that sodium cholate has superiority as a penetration enhancer over sodium taurocholate in terms of morphological characterizes, zeta potential, and cumulative amounts of tamoxifen permeated per unit area (15.13 ± 0.71 μg/cm2 and 6.51 ± 0.6 μg/cm2 respectively). In fact, bilosomes designed with sodium cholate provided around 9 folds of skin deposition compared to TXN non-bilosomal gel.

    CONCLUSION: Bilosomes gels could be a promising option for locally delivering tamoxifen to the breast through the skin, offering an encouraging transdermal solution.

  14. Fulltext Potential inhibitors for isocitrate lyase of Mycobacterium tuberculosis and non-M. tuberculosis: a summary
    Lee YV, Wahab HA, Choong YS
    Biomed Res Int, 2015;2015:895453.
    PMID: 25649791 DOI: 10.1155/2015/895453
    Isocitrate lyase (ICL) is the first enzyme involved in glyoxylate cycle. Many plants and microorganisms are relying on glyoxylate cycle enzymes to survive upon downregulation of tricarboxylic acid cycle (TCA cycle), especially Mycobacterium tuberculosis (MTB). In fact, ICL is a potential drug target for MTB in dormancy. With the urge for new antitubercular drug to overcome tuberculosis treat such as multidrug resistant strain and HIV-coinfection, the pace of drug discovery has to be increased. There are many approaches to discovering potential inhibitor for MTB ICL and we hereby review the updated list of them. The potential inhibitors can be either a natural compound or synthetic compound. Moreover, these compounds are not necessary to be discovered only from MTB ICL, as it can also be discovered by a non-MTB ICL. Our review is categorized into four sections, namely, (a) MTB ICL with natural compounds; (b) MTB ICL with synthetic compounds; (c) non-MTB ICL with natural compounds; and (d) non-MTB ICL with synthetic compounds. Each of the approaches is capable of overcoming different challenges of inhibitor discovery. We hope that this paper will benefit the discovery of better inhibitor for ICL.
  15. Applications of Ensemble Docking in Potential Inhibitor Screening for Mycobacterium tuberculosis Isocitrate Lyase Using a Local Plant Database
    Lee YV, Choi SB, Wahab HA, Lim TS, Choong YS
    J Chem Inf Model, 2019 05 28;59(5):2487-2495.
    PMID: 30840452 DOI: 10.1021/acs.jcim.8b00963
    Isocitrate lyase (ICL) is a persistent factor for the survival of dormant stage Mycobacterium tuberculosis (MTB), thus a potential drug target for tuberculosis treatment. In this work, ensemble docking approach was used to screen for potential inhibitors of ICL. The ensemble conformations of ICL active site were obtained from molecular dynamics simulation on three dimer form systems, namely the apo ICL, ICL in complex with metabolites (glyoxylate and succinate), and ICL in complex with substrate (isocitrate). Together with the ensemble conformations and the X-ray crystal structures, 22 structures were used for the screening against Malaysian Natural Compound Database (NADI). The top 10 compounds for each ensemble conformation were selected. The number of compounds was then further narrowed down to 22 compounds that were within the Lipinski's Rule of Five for drug-likeliness and were also docked into more than one ensemble conformation. Theses 22 compounds were furthered evaluate using whole cell assay. Some compounds were not commercially available; therefore, plant crude extracts were used for the whole cell assay. Compared to itaconate (the known inhibitor of ICL), crude extracts from Manilkara zapota, Morinda citrifolia, Vitex negundo, and Momordica charantia showed some inhibition activity. The MIC/MBC value were 12.5/25, 12.5/25, 0.78/1.6, and 0.39/1.6 mg/mL, respectively. This work could serve as a preliminary study in order to narrow the scope for high throughput screening in the future.
  16. Active Site Flexibility of Mycobacterium tuberculosis Isocitrate Lyase in Dimer Form
    Lee YV, Choi SB, Wahab HA, Choong YS
    J Chem Inf Model, 2017 09 25;57(9):2351-2357.
    PMID: 28820943 DOI: 10.1021/acs.jcim.7b00265
    Tuberculosis (TB) still remains a global threat due to the emergence of a drug-resistant strain. Instead of focusing on the drug target of active stage TB, we are highlighting the isocitrate lyase (ICL) at the dormant stage TB. ICL is one of the persistent factors for Mycobacterium tuberculosis (MTB) to survive during the dormant phase. In addition, the absence of ICL in human has made ICL a potential drug target for TB therapy. However, the dynamic details of ICL which could give insights to the ICL-ligand interaction have yet to be solved. Therefore, a series of ICL dimer dynamics studies through molecular dynamics simulation were performed in this work. The ICL active site entrance gate closure is contributed to by hydrogen bonding and electrostatic interactions with the C-terminal. Analysis suggested that the open-closed behavior of the ICL active site entrance depends on the type of ligand present in the active site. We also observed four residues (Ser91, Asp108, Asp153, and Cys191) which could possibly be the nucleophiles for nucleophilic attack on the cleavage of isocitrate at the C2-C3bond. We hope that the elucidation of ICL dynamics can benefit future works such as lead identification or antibody design against ICL for TB therapeutics.
  17. Women in Computational Chemistry
    Wahab HA, Amaro RE, Cournia Z
    J Chem Inf Model, 2018 11 26;58(11):2175-2177.
    PMID: 30277769 DOI: 10.1021/acs.jcim.8b00642
  18. Fulltext Structural modeling and biochemical characterization of recombinant KPN_02809, a zinc-dependent metalloprotease from Klebsiella pneumoniae MGH 78578
    Wong MT, Choi SB, Kuan CS, Chua SL, Chang CH, Normi YM, et al.
    Int J Mol Sci, 2012;13(1):901-17.
    PMID: 22312293 DOI: 10.3390/ijms13010901
    Klebsiella pneumoniae is a Gram-negative, cylindrical rod shaped opportunistic pathogen that is found in the environment as well as existing as a normal flora in mammalian mucosal surfaces such as the mouth, skin, and intestines. Clinically it is the most important member of the family of Enterobacteriaceae that causes neonatal sepsis and nosocomial infections. In this work, a combination of protein sequence analysis, structural modeling and molecular docking simulation approaches were employed to provide an understanding of the possible functions and characteristics of a hypothetical protein (KPN_02809) from K. pneumoniae MGH 78578. The computational analyses showed that this protein was a metalloprotease with zinc binding motif, HEXXH. To verify this result, a ypfJ gene which encodes for this hypothetical protein was cloned from K. pneumoniae MGH 78578 and the protein was overexpressed in Escherichia coli BL21 (DE3). The purified protein was about 32 kDa and showed maximum protease activity at 30 °C and pH 8.0. The enzyme activity was inhibited by metalloprotease inhibitors such as EDTA, 1,10-phenanthroline and reducing agent, 1,4-dithiothreitol (DTT). Each molecule of KPN_02809 protein was also shown to bind one zinc ion. Hence, for the first time, we experimentally confirmed that KPN_02809 is an active enzyme with zinc metalloprotease activity.
  19. Fulltext Klebsiella pneumoniae yggG gene product: a zinc-dependent metalloprotease
    Kuan CS, Wong MT, Choi SB, Chang CC, Yee YH, Wahab HA, et al.
    Int J Mol Sci, 2011;12(7):4441-55.
    PMID: 21845088 DOI: 10.3390/ijms12074441
    Klebsiella pneumoniae causes neonatal sepsis and nosocomial infections. One of the strains, K. pneumoniae MGH 78578, shows high level of resistance to multiple microbial agents. In this study, domain family, amino acid sequence and topology analyses were performed on one of its hypothetical protein, YggG (KPN_03358). Structural bioinformatics approaches were used to predict the structure and functionality of YggG protein. The open reading frame (ORF) of yggG, which was a putative metalloprotease gene, was also cloned, expressed and characterized. The ORF was PCR amplified from K. pneumoniae MGH 78578 genomic DNA and cloned into a pET14-b vector for heterologous expression in Escherichia coli. The purified YggG protein was subsequently assayed for casein hydrolysis under different conditions. This protein was classified as peptidase M48 family and subclan gluzincin. It was predicted to contain one transmembrane domain by TMpred. Optimal protein expression was achieved by induction with 0.6 mM isopropyl thiogalactoside (IPTG) at 25 °C for six hours. YggG was purified as soluble protein and confirmed to be proteolytically active under the presence of 1.25 mM zinc acetate and showed optimum activity at 37 °C and pH 7.4. We confirmed for the first time that the yggG gene product is a zinc-dependent metalloprotease.
  20. Binding specificity of polypeptide substrates in NS2B/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study
    Yotmanee P, Rungrotmongkol T, Wichapong K, Choi SB, Wahab HA, Kungwan N, et al.
    J Mol Graph Model, 2015 Jul;60:24-33.
    PMID: 26086900 DOI: 10.1016/j.jmgm.2015.05.008
    The pathogenic dengue virus (DV) is a growing global threat, particularly in South East Asia, for which there is no specific treatment available. The virus possesses a two-component (NS2B/NS3) serine protease that cleaves the viral precursor proteins. Here, we performed molecular dynamics simulations of the NS2B/NS3 protease complexes with six peptide substrates (capsid, intNS3, 2A/2B, 4B/5, 3/4A and 2B/3 containing the proteolytic site between P(1) and P(1)' subsites) of DV type 2 to compare the specificity of the protein-substrate binding recognition. Although all substrates were in the active conformation for cleavage reaction by NS2B/NS3 protease, their binding strength was somewhat different. The simulated results of intermolecular hydrogen bonds and decomposition energies suggested that among the ten substrate residues (P(5)-P(5)') the P(1) and P(2) subsites play a major role in the binding with the focused protease. The arginine residue at these two subsites was found to be specific preferential binding at the active site with a stabilization energy of intNS3>2A/2B>4B/5>3/4A>2B/3 in a relative correspondence with previous experimentally derived values.
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