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Ngoh Y.-Y.,Universiti Sains Malaysia | Choi S.B.,Malaysian Institutes of Pharmaceuticals and Nutraceuticals | Gan C.-Y.,Universiti Sains Malaysia
Journal of Functional Foods | Year: 2017

The aim of the study was to explore the physiological effects of Pinto bean peptides (PBP) and their structure-activity relationships. Five pre-screened PBPs were investigated. The results showed that PBPs enhanced the protease activity ranging from 333 to 400%, and conversely, they inhibited lipase activity ranging from ∼23 to ∼87%. It was suggested that the binding of PBP to pepsin (i.e. Asp52, Tyr113 and Tyr114) resulted in a broad flap extension and enlarged the S3 pocket, which made the active site more accessible, whereas, catalytic residues (i.e. Ser153 and His264) of lipase were found strongly bound to PBPs and preventing the enzyme from hydrolysing lipids. PBPs also shown their ability in binding bile acid ranging from ∼18 to ∼71% via hydrogen bonds to the C5-OH, C11-OH, C15-OH or C21-OH of cholic acid and deoxycholic acid. This study highlighted the effectiveness and mechanism of PBP in preventing obesity, hyperlipidaemia and hypercholesterolemia. © 2017 Elsevier Ltd


Yotmanee P.,Ramkhamhaeng University | Yotmanee P.,Chulalongkorn University | Rungrotmongkol T.,Chulalongkorn University | Wichapong K.,Chulalongkorn University | And 6 more authors.
Journal of Molecular Graphics and Modelling | Year: 2015

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 P1 and P1′ 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 (P5-P5′) the P1 and P2 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 <-10 kcal mol-1. Besides, the P3, P1′, P2′ and P4′ subsites showed a less contribution in binding interaction (<-2 kcal mol-1). The catalytic water was detected nearby the carbonyl oxygen of the P1 reacting center of the capsid, intNS3, 2A/2B and 4B/5 peptides. These results led to the order of absolute binding free energy (ΔGbind) between these substrates and the NS2B/NS3 protease ranked as capsid > intNS3 > 2A/2B > 4B/5 > 3/4A > 2B/3 in a relative correspondence with previous experimentally derived values. © 2015 Elsevier Inc. All rights reserved.


Choi S.B.,Malaysian Institutes of Pharmaceuticals and Nutraceuticals | Choi S.B.,Universiti Sains Malaysia | Choong Y.S.,Universiti Sains Malaysia | Saito A.,Osaka Electro-Communication University | And 8 more authors.
Molecular Informatics | Year: 2014

Present HIV antiviral therapy only targets structural proteins of HIV, but evidence shows that the targeting of accessory proteins will expand our options in combating HIV. HIV-1 Vpr, a multifunctional accessory protein involved in viral infection, replication and pathogenesis, is a potential target. Previously, we have shown that phenyl coumarin compounds can inhibit the growth arrest activity of Vpr in host cells and predicted that the inhibitors' binding site is a hydrophobic pocket on Vpr. To investigate our prediction of the inhibitors' binding site, we docked the coumarin inhibitors into the predicted hydrophobic binding pocket on a built model of Vpr and observed a linear trend between their calculated binding energies and prior experimentally determined potencies. Subsequently, to analyze the inhibitor-protein binding interactions in detail, we built homology models of Vpr mutants and performed docking studies on these models too. The results revealed that structural changes on the binding pocket that were caused by the mutations affected inhibitor binding. Overall, this study showed that the binding energies of the docked molecules are good indicators of the activity of the inhibitors. Thus, the model can be used in virtual screening to identify other Vpr inhibitors and for designing more potent inhibitors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Lee Y.-V.,Universiti Sains Malaysia | Wahab H.A.,Universiti Sains Malaysia | Wahab H.A.,Malaysian Institutes of Pharmaceuticals and Nutraceuticals | Choong Y.S.,Universiti Sains Malaysia
BioMed Research International | Year: 2015

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. © 2015 Yie-Vern Lee et al.


PubMed | Malaysian Institutes of Pharmaceuticals and Nutraceuticals and International Medical University
Type: Journal Article | Journal: Interdisciplinary sciences, computational life sciences | Year: 2015

Heat shock proteins (Hsps) 60 and 70 are postulated as a potential drug target for toxoplasmosis due to its importance in the developmental and survival of Toxoplasma gondii (T. gondii). As of today, there have been no reports on three-dimensional (3D) structure of Hsp60 and Hsp70 deposited in the Brookhaven Protein Data Bank. Hence, this study was conducted to predict 3D structures for Hsp60 and Hsp70 in T. gondii by homology modeling. Selection of the best predicted model was done based on multiple scoring functions. In addition, virtual screening was performed to short-list chemical compounds from the National Cancer Institute (NCI) Diversity Set III in search of potential inhibitor against Hsp60 and Hsp70 in T. gondii. Prior to virtual screening, binding sites of Hsp60 and Hsp70 were predicted using various servers and were used as the center in docking studies. The Hsps were docked against known natural ligands to validate the method used in estimating free energy of binding (FEB) and possible interactions between ligand and protein. Virtual screening was performed with a total of 1560 compounds from the NCI Diversity Set III. The compounds were ranked subsequently according to their FEB. Molecular basis of interactions of the top five ranked compounds was investigated using Ligplot

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