Displaying publications 1 - 20 of 87 in total

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  1. Osman H, Idris NH, Kamarulzaman EE, Wahab HA, Hassan MZ
    Acta Pharm Sin B, 2017 Jul;7(4):479-484.
    PMID: 28752033 DOI: 10.1016/j.apsb.2017.04.009
    Dengue is a severe mosquito-borne viral infection causing half a million deaths annually. Dengue virus NS2B/NS3 protease is a validated target for anti-dengue drug design. A series of hitherto unreported 3,5-bis(arylidene)-4-piperidones analogues 4a-4j were synthesized and screened in silico against DENV2 NS2B/NS3 protease to elucidate their binding mechanism and orientation around the active sites. Results were validated through an in vitro DENV2 NS2B/NS3 protease assay using a fluorogenic Boc-Gly-Arg-Arg-AMC substrate. Nitro derivatives of 3,5-bis(arylidene)-4-piperidones (4e and 4j) emerged as promising lead molecules for novel protease inhibitors with an IC50 of 15.22 and 16.23 µmol/L, respectively, compared to the standard, panduratin A, having IC50 of 57.28 µmol/L.
  2. Hariono M, Wahab HA, Tan ML, Rosli MM, Razak IA
    PMID: 24764997 DOI: 10.1107/S1600536814001986
    In the title compound, C19H17N5S, the dihedral angles between the purine ring system (r.m.s. deviation = 0.009 Å) and the S-bound and methyl-ene-bound phenyl rings are 74.67 (8) and 71.28 (7)°, respectively. In the crystal, inversion dimers linked by pairs of N-H⋯N hydrogen bonds generate R 2 (2)(8) loops. C-H⋯N inter-actions link the dimers into (100) sheets.
  3. Rawa MSA, Nogawa T, Okano A, Futamura Y, Nakamura T, Wahab HA, et al.
    Biosci Biotechnol Biochem, 2021 Jan 07;85(1):69-76.
    PMID: 33577647 DOI: 10.1093/bbb/zbaa051
    A new peptaibol, RK-026A (1) was isolated from a fungus, Trichoderma sp. RK10-F026, along with atroviridin B (2), alamethicin II (3), and polysporin B (4) as a cytotoxic compound, which was selected by principal component analysis of the MS data from 5 different culture conditions. The structure of 1 was determined as a new atroviridin B derivative containing Glu at the 18th residue instead of Gln by NMR and HR-MS analyses including the investigation of detailed MS/MS fragmentations. 1 showed cytotoxicity toward K562 leukemia cells at an IC50 value of 4.1 µm.
  4. Hariyono P, Kotta JC, Adhipandito CF, Aprilianto E, Candaya EJ, Wahab HA, et al.
    Appl Biol Chem, 2021;64(1):69.
    PMID: 34549099 DOI: 10.1186/s13765-021-00639-w
    The H1N1 pandemic in 2009 and the H5N1 outbreak in 2005 have shocked the world as millions of people were infected and hundreds of thousands died due to the infections by the influenza virus. Oseltamivir, the most common drug to block the viral life cycle by inhibiting neuraminidase (NA) enzyme, has been less effective in some resistant cases due to the virus mutation. Presently, the binding of 10 chalcone derivatives towards H5N1 and H1N1 NAs in the non-catalytic and catalytic sites was studied using molecular docking. The in silico study was also conducted for its drug-like likeness such as Lipinski Rule, mutagenicity, toxicity and pharmacokinetic profiles. The result demonstrates that two chalcones (1c and 2b) have the potential for future NA inhibitor development. Compound 1c inhibits H5N1 NA and H1N1 NA with IC50 of 27.63 µM and 28.11 µM, respectively, whereas compound 2b inhibits NAs with IC50 of 87.54 µM and 73.17 µM for H5N1 and H1N1, respectively. The in silico drug-like likeness prediction reveals that 1c is 62% better than 2b (58%) in meeting the criteria. The results suggested that 1c and 2b have potencies to be developed as non-competitive inhibitors of neuraminidase for the future development of anti-influenza drugs.

    Supplementary Information: The online version contains supplementary material available at 10.1186/s13765-021-00639-w.

  5. Ikram NK, Durrant JD, Muchtaridi M, Zalaludin AS, Purwitasari N, Mohamed N, et al.
    J Chem Inf Model, 2015 Feb 23;55(2):308-16.
    PMID: 25555059 DOI: 10.1021/ci500405g
    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.
  6. 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.
  7. Mohtar N, Parumasivam T, Gazzali AM, Tan CS, Tan ML, Othman R, et al.
    Cancers (Basel), 2021 Jul 15;13(14).
    PMID: 34298753 DOI: 10.3390/cancers13143539
    Lung cancers, the number one cancer killer, can be broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC being the most commonly diagnosed type. Anticancer agents for NSCLC suffer from various limitations that can be partly overcome by the application of nanomedicines. Nanoparticles is a branch within nanomedicine that can improve the delivery of anticancer drugs, whilst ensuring the stability and sufficient bioavailability following administration. There are many publications available in the literature exploring different types of nanoparticles from different materials. The effectiveness of a treatment option needs to be validated in suitable in vitro and/or in vivo models. This includes the developed nanoparticles, to prove their safety and efficacy. Many researchers have turned towards in vitro models that use normal cells or specific cells from diseased tissues. However, in cellular works, the physiological dynamics that is available in the body could not be mimicked entirely, and hence, there is still possible development of false positive or false negative results from the in vitro models. This article provides an overview of NSCLC, the different nanoparticles available to date, and in vitro evaluation of the nanoparticles. Different types of cells suitable for in vitro study and the important precautions to limit the development of false results are also extensively discussed.
  8. 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
  9. Othman R, Wahab HA, Yusof R, Rahman NA
    In Silico Biol. (Gedrukt), 2007;7(2):215-24.
    PMID: 17688447
    Multiple sequence alignment was performed against eight proteases from the Flaviviridae family using ClustalW to illustrate conserved domains. Two sets of prediction approaches were applied and the results compared. Firstly, secondary structure prediction was performed using available structure prediction servers. The second approach made use of the information on the secondary structures extracted from structure prediction servers, threading techniques and DSSP database of some of the templates used in the threading techniques. Consensus on the one-dimensional secondary structure of Den2 protease was obtained from each approach and evaluated against data from the recently crystallised Den2 NS2B/NS3 obtained from the Protein Data Bank (PDB). Results indicated the second approach to show higher accuracy compared to the use of prediction servers only. Thus, it is plausible that this approach is applicable to the initial stage of structural studies of proteins with low amino acid sequence homology against other available proteins in the PDB.
  10. Riswanto FDO, Rawa MSA, Murugaiyah V, Salin NH, Istyastono EP, Hariono M, et al.
    Med Chem, 2021;17(5):442-452.
    PMID: 31808389 DOI: 10.2174/1573406415666191206095032
    BACKGROUND: Chalcones, originated from natural product, have been broadly studied their biological activity against various proteins which at the molecular level, are responsible for the progress of the diseases in cancer (e.g. kinases), inflammation (oxidoreductases), atherosclerosis (cathepsins receptor), and diabetes (e.g. α-glucosidase).

    OBJECTIVE: Here we synthesize 10 chalcone derivatives to be evaluated their in vitro enzymatic inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE).

    METHODS: The synthesis was carried out using Claissen-Schimdt condensation and the in vitro assay was conducted using Ellman Method.

    RESULTS: Compounds 2b and 4b demonstrated as the best IC50 of 9.3 μM and 68.7 μM respectively, towards AChE and BChE inhibition. Molecular docking studies predicted that this activity might be due to the interaction of the chalcones with important amino acid residues in the binding site of AChE such as SER200 and in that of BChE, such as TRP82, SER198, TRP430, TYR440, LEU286 and VAL288.

    CONCLUSION: Chalcone can be used as the scaffold for cholinesterase inhibitor, in particularly either fluorine or nitro group to be augmented at the para-position of Ring B, whereas the hydrophobic chain is necessary at the meta-position of Ring B.

  11. Amir Rawa MS, Hassan Z, Murugaiyah V, Nogawa T, Wahab HA
    J Ethnopharmacol, 2019 Dec 05;245:112160.
    PMID: 31419500 DOI: 10.1016/j.jep.2019.112160
    ETHNOPHARMACOLOGICAL RELEVANCE: Enhancement of cholinergic functions in the brain via acetylcholinesterase inhibition is one of the main therapeutic strategies to improve symptoms associated with Alzheimer's or related cognitive deficits. There is a pathophysiological correlation between Alzheimer's and Diabetes Mellitus, as well as inflammation and oxidative stress that may cause cognitive decline.

    AIM OF THE STUDY: The present study was intended to evaluate anti-cholinesterase potential of 177 Malaysian plant extracts from 148 species known to have related ethnomedicinal uses such as anti-inflammatory, anti-oxidant, anti-diabetic, epilepsy, headache, memory enhancement and anti-aging.

    MATERIALS AND METHODS: Anti-cholinesterase screening against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes was performed on the basis of in-vitro colorimetric 96-well microplate-based assay method. Potent active plant extracts were subjected to liquid-liquid extraction and acid-base fractionation for further analysis.

    RESULTS: Fifty-seven plant extracts exhibited potent anti-cholinesterase activities (50-100% inhibition) at 200 μg/ml. Majority of the active plants originated from Fabaceae family. Coccoloba uvifera (L.) L. stem extract manifested the lowest IC50 of 3.78 μg/ml for AChE and 5.94 μg/ml for BChE. A few native species including Tetracera indica (Christm. & Panz.) Merr., Cyrtostachys renda Blume and Ixora javanica (Blume) DC. showed cholinesterase inhibition despite limited local medical applications. Further anti-AChE evaluation (50 μg/ml) of 18 potent plant extracts harbored active polar components in butanol and water fractions, except Senna pendula (Willd.) H.S.Irwin & Barneby (leaves and stems), Acacia auriculiformis Benth. (leaves), Artocarpus altilis (Parkinson ex F.A.Zorn) Fosberg (leaves), and Macaranga tanarius (L.) Mull.Arg. (leaves) that showed inhibitory activity in less polar fractions. The acidic extraction of these four plant species improved their inhibition level against AChE.

    CONCLUSION: This study rendered a preliminary overview of anti-cholinesterase activity from diverse Malaysian botanical families in which provided the medical relevance toward these native plant species, especially ones with limited ethnobotanical record or practice.

  12. Alhawarri MB, Dianita R, Razak KNA, Mohamad S, Nogawa T, Wahab HA
    Molecules, 2021 Apr 29;26(9).
    PMID: 33946788 DOI: 10.3390/molecules26092594
    Despite being widely used traditionally as a general tonic, especially in South East Asia, scientific research on Cassia timoriensis, remains scarce. In this study, the aim was to evaluate the in vitro activities for acetylcholinesterase (AChE) inhibitory potential, radical scavenging ability, and the anti-inflammatory properties of different extracts of C. timoriensis flowers using Ellman's assay, a DPPH assay, and an albumin denaturation assay, respectively. With the exception of the acetylcholinesterase activity, to the best of our knowledge, these activities were reported for the first time for C. timoriensis flowers. The phytochemical analysis confirmed the existence of tannins, flavonoids, saponins, terpenoids, and steroids in the C. timoriensis flower extracts. The ethyl acetate extract possessed the highest phenolic and flavonoid contents (527.43 ± 5.83 mg GAE/g DW and 851.83 ± 10.08 mg QE/g DW, respectively) as compared to the other extracts. In addition, the ethyl acetate and methanol extracts exhibited the highest antioxidant (IC50 20.12 ± 0.12 and 34.48 ± 0.07 µg/mL, respectively), anti-inflammatory (92.50 ± 1.38 and 92.22 ± 1.09, respectively), and anti-AChE (IC50 6.91 ± 0.38 and 6.40 ± 0.27 µg/mL, respectively) activities. These results suggest that ethyl acetate and methanol extracts may contain bioactive compounds that can control neurodegenerative disorders, including Alzheimer's disease, through high antioxidant, anti-inflammatory, and anti-AChE activities.
  13. Mazlan MKN, Mohd Tazizi MHD, Ahmad R, Noh MAA, Bakhtiar A, Wahab HA, et al.
    Antibiotics (Basel), 2021 Jul 25;10(8).
    PMID: 34438958 DOI: 10.3390/antibiotics10080908
    Mycobacterium tuberculosis (Mtb) is the microorganism that causes tuberculosis. This infectious disease has been around for centuries, with the earliest record of Mtb around three million years ago. The discovery of the antituberculosis agents in the 20th century has managed to improve the recovery rate and reduce the death rate tremendously. However, the conventional antituberculosis therapy is complicated by the development of resistant strains and adverse drug reactions experienced by the patients. Research has been conducted continuously to discover new, safe, and effective antituberculosis drugs. In the last 50 years, only two molecules were approved despite laborious work and costly research. The repurposing of drugs is also being done with few drugs; antibiotics, particularly, were found to have antituberculosis activity. Besides the discovery work, enhancing the delivery of currently available antituberculosis drugs is also being researched. Targeted drug delivery may be a potentially useful approach to be developed into clinically accepted treatment modalities. Active targeting utilizes a specifically designed targeting agent to deliver a chemically conjugated drug(s) towards Mtb. Passive targeting is very widely explored, with the development of multiple types of nanoparticles from organic and inorganic materials. The nanoparticles will be engulfed by macrophages and this will eliminate the Mtb that is present in the macrophages, or the encapsulated drug may be released at the sites of infections that may be in the form of intra- and extrapulmonary tuberculosis. This article provided an overview on the history of tuberculosis and the currently available treatment options, followed by discussions on the discovery of new antituberculosis drugs and active and passive targeting approaches against Mycobacterium tuberculosis.
  14. Mohamad S, Zin NM, Wahab HA, Ibrahim P, Sulaiman SF, Zahariluddin AS, et al.
    J Ethnopharmacol, 2011 Feb 16;133(3):1021-6.
    PMID: 21094237 DOI: 10.1016/j.jep.2010.11.037
    Many local plants are used in Malaysian traditional medicine to treat respiratory diseases including symptoms of tuberculosis. The aim of the study was to screen 78 plant extracts from 70 Malaysian plant species used in traditional medicine to treat respiratory diseases including symptoms of tuberculosis for activity against Mycobacterium tuberculosis H37Rv using a colorimetric microplate-based assay.
  15. 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. Hariono M, Nuwarda RF, Yusuf M, Rollando R, Jenie RI, Al-Najjar B, et al.
    J Chem Inf Model, 2020 01 27;60(1):349-359.
    PMID: 31825614 DOI: 10.1021/acs.jcim.9b00630
    Previous studies have reported that compounds bearing an arylamide linked to a heterocyclic planar ring have successfully inhibited the hemopexin-like domain (PEX9) of matrix metalloproteinase 9 (MMP9). PEX9 has been suggested to be more selectively targeted than MMP9's catalytic domain in a degrading extracellular matrix under some pathologic conditions, especially in cancer. In this study, we aim to synthesize and evaluate 10 arylamide compounds as MMP9 inhibitors through an enzymatic assay as well as a cellular assay. The mechanism of inhibition for the most active compounds was investigated via molecular dynamics simulation (MD). Molecular docking was performed using AutoDock4.0 with PEX9 as the protein model to predict the binding of the designed compounds. The synthesis was carried out by reacting aniline derivatives with 3-bromopropanoyl chloride using pyridine as the catalyst at room temperature. The MMP9 assay was conducted using the FRET-based MMP9 kits protocol and gelatin zymography assay. The cytotoxicity assay was done using the MTT method, and the MD simulation was performed using AMBER16. Assay on MMP9 demonstrated activities of three compounds (2, 7, and 9) with more than 50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed that two compounds (7 and 9) inhibited its gelatinolytic activity more than 50%. The cytotoxicity assay against 4T1 cells results in the inhibition of the cell growth with an EC50 of 125 μM and 132 μM for 7 and 9, respectively. The MD simulation explained a stable interaction of 7 and 9 in PEX9 at 100 ns with a free energy of binding of -8.03 kcal/mol and -6.41 kcal/mol, respectively. Arylamides have potential effects as selective MMP9 inhibitors in inhibiting breast cancer cell progression.
  17. Norshidah H, Leow CH, Ezleen KE, Wahab HA, Vignesh R, Rasul A, et al.
    Front Cell Infect Microbiol, 2023;13:1061937.
    PMID: 36864886 DOI: 10.3389/fcimb.2023.1061937
    An increase in the occurrence of viral infectious diseases is a global concern for human health. According to a WHO report, dengue virus (DENV) is one of the most common viral diseases affecting approximately 400 million people annually, with worsening symptoms in nearly 1% of cases. Both academic and industrial researchers have conducted numerous studies on viral epidemiology, virus structure and function, source and route of infection, treatment targets, vaccines, and drugs. The development of CYD-TDV or Dengvaxia® vaccine has been a major milestone in dengue treatment. However, evidence has shown that vaccines have some drawbacks and limitations. Therefore, researchers are developing dengue antivirals to curb infections. DENV NS2B/NS3 protease is a DENV enzyme essential for replication and virus assembly, making it an interesting antiviral target. For faster hit and lead recognition of DENV targets, methods to screen large number of molecules at lower costs are essential. Similarly, an integrated and multidisciplinary approach involving in silico screening and confirmation of biological activity is required. In this review, we discuss recent strategies for searching for novel DENV NS2B/NS3 protease inhibitors from the in silico and in vitro perspectives, either by applying one of the approaches or by integrating both. Therefore, we hope that our review will encourage researchers to integrate the best strategies and encourage further developments in this area.
  18. 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.
  19. 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.

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