Displaying publications 41 - 60 of 302 in total

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  1. Evaluating the performance of MM/PBSA for binding affinity prediction using class A GPCR crystal structures
    Yau MQ, Emtage AL, Chan NJY, Doughty SW, Loo JSE
    J Comput Aided Mol Des, 2019 05;33(5):487-496.
    PMID: 30989574 DOI: 10.1007/s10822-019-00201-3
    The recent expansion of GPCR crystal structures provides the opportunity to assess the performance of structure-based drug design methods for the GPCR superfamily. Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA)-based methods are commonly used for binding affinity prediction, as they provide an intermediate compromise of speed and accuracy between the empirical scoring functions used in docking and more robust free energy perturbation methods. In this study, we systematically assessed the performance of MM/PBSA in predicting experimental binding free energies using twenty Class A GPCR crystal structures and 934 known ligands. Correlations between predicted and experimental binding free energies varied significantly between individual targets, ranging from r = - 0.334 in the inactive-state CB1 cannabinoid receptor to r = 0.781 in the active-state CB1 cannabinoid receptor, while average correlation across all twenty targets was relatively poor (r = 0.183). MM/PBSA provided better predictions of binding free energies compared to docking scores in eight out of the twenty GPCR targets while performing worse for four targets. MM/PBSA binding affinity predictions calculated using a single, energy minimized structure provided comparable predictions to sampling from molecular dynamics simulations and may be more efficient when computational cost becomes restrictive. Additionally, we observed that restricting MM/PBSA calculations to ligands with a high degree of structural similarity to the crystal structure ligands improved performance in several cases. In conclusion, while MM/PBSA remains a valuable tool for GPCR structure-based drug design, its performance in predicting the binding free energies of GPCR ligands remains highly system-specific as demonstrated in a subset of twenty Class A GPCRs, and validation of MM/PBSA-based methods for each individual case is recommended before prospective use.
    Matched MeSH terms: Protein Binding
  2. Fulltext IFN-γ Induction of Apolipoprotein A-I Expression is Mediated by NF-κB Signalling in HepG2 Cells
    Lui Siang Tong, Hong Kin Wong, Choy Hoong Chew
    Trop Life Sci Res, 2019;30(2):1-13.
    MyJurnal
    Keradangan hati berkait rapat dengan perubahan dalam ekspresi lipoprotein dan apolipoprotein. Interferon-γ (IFN-γ), wakil tunggal jenis kedua IFN, memainkan peranan yang penting dalam memodulasi dan mempergiatkan tindak balas keradangan. Justeru itu, kajian ini direka untuk mengenal pasti kesan IFN-γ terhadap apolipoprotein A-I (APOA-I) dan penglibatan nuclear factor–kappa B (NF-κB) dalam laluan isyarat tersebut. Tindak balas rantai polymerase transkripsi berbalik kuantitatif (qRT-PCR) dan analisis blot western telah dilaksanakan untuk menguantifikasi ekspresi APOA-I dalam sel-sel HepG2 selepas dirawat dengan IFN-γ. Kajian ini menunjukkan bahawa 50 ng/mL IFN-γ merangsangkan ekspresi mRNA dan protein APOA-I. Walau bagaimanapun, pra-rawatan sel dengan inhibitor laluan isyarat NF-κB mengurangkan tahap ekspresi APOA-I. Kajian ini juga mendemonstrasikan penglibatan langsung isyarat NF-κB dalam ekspresi APOA-I akibat rangsangan IFN-γ, di mana IFN-γ meningkatkan tahap fosforilasi NF-κB p65 Ser468 dan Ser536 kepada 2.59-ganda and 1.63-ganda. Namun demikian, pra-rawatan sel dengan perencat laluan isyarat NF-κB melumpuhkan peningkatkan tersebut dan kemudian mengurangkan ekspresi APOA-I dalam sel HepG2. Sebagai rumusan, kajian ini berjaya mengenalpasti peranan isyarat NF-κB dan pengaktifan p65 Ser468 dan Ser536 sebagai pengantara IFN-γ ke atas induksi APOA-I di dalam sel-sel HepG2.
    Matched MeSH terms: Protein Binding
  3. Biophysical and computational view on the in vitro combination between an anticancer drug, saracatinib and human serum albumin
    Tayyab S, Magesvaran MKA, Kabir MZ, Ridzwan NFW, Mohamad SB
    J Biomol Struct Dyn, 2021 Jul;39(10):3565-3575.
    PMID: 32397949 DOI: 10.1080/07391102.2020.1766571
    Interaction behaviour of an anticancer drug, saracatinib (SCB) with human serum albumin (HSA), the major carrier protein in human blood circulation was investigated using fluorescence and absorption spectroscopy as well as computational methods. Analysis of the fluorescence quenching data along with absorption results confirmed the complex formation between SCB and HSA, based on the inverse correlation of the Stern-Volmer constant (KSV) with temperature and hyperchromic effect in the absorption spectra. Moderate binding affinity between SCB and HSA was evident from the binding constant, Ka value (1.08-0.74 × 104 M-1), while the SCB-HSA complexation was anticipated to be stabilized by hydrophobic and van der Waals interactions along with hydrogen bonds, as revealed from the thermodynamic data (ΔS = + 29.40 J mol-1 K-1 and ΔH = - 13.90 kJ mol-1). Addition of SCB to HSA significantly defended the thermal denaturation of the protein, though it perturbed the surrounding medium around Tyr and Trp residues. Site marker displacement results elucidated Sudlow's site I, positioned in subdomain IIA of HSA as the preferred binding site of SCB, which was well supported by molecular docking. Molecular dynamics simulation results suggested the stability of the SCB-HSA complex.Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Protein Binding
  4. Evaluation of pendimethalin binding to human serum albumin: Insights from spectroscopic and molecular modeling approach
    Lee WQ, Affandi IS, Feroz SR, Mohamad SB, Tayyab S
    J Biochem Mol Toxicol, 2017 Feb;31(2).
    PMID: 27636401 DOI: 10.1002/jbt.21839
    Interaction of pendimethalin (PM) herbicide with the major transporter in human circulation, human serum albumin (HSA), was studied using fluorescence, circular dichroism (CD), and molecular modeling methods. The attenuation of the fluorescence intensity of HSA in the presence of PM revealed formation of the PM-HSA complex. Analysis of the fluorescence quenching data showed moderately strong binding affinity between PM and HSA. Both hydrophobic interactions and hydrogen bonding were suggested to stabilize the PM-HSA complex, based on thermodynamic data. Binding of PM to HSA induced perturbation in the microenvironment around the aromatic fluorophores as well as secondary and tertiary structural changes in the protein. Complexation of PM with HSA led to an increase in its thermal stability. Both site marker displacement and molecular modeling results suggested site I, located in subdomain IIA as the preferred binding site of PM on HSA.
    Matched MeSH terms: Protein Binding
  5. Fulltext AnkPlex: algorithmic structure for refinement of near-native ankyrin-protein docking
    Wisitponchai T, Shoombuatong W, Lee VS, Kitidee K, Tayapiwatana C
    BMC Bioinformatics, 2017 Apr 19;18(1):220.
    PMID: 28424069 DOI: 10.1186/s12859-017-1628-6
    BACKGROUND: Computational analysis of protein-protein interaction provided the crucial information to increase the binding affinity without a change in basic conformation. Several docking programs were used to predict the near-native poses of the protein-protein complex in 10 top-rankings. The universal criteria for discriminating the near-native pose are not available since there are several classes of recognition protein. Currently, the explicit criteria for identifying the near-native pose of ankyrin-protein complexes (APKs) have not been reported yet.

    RESULTS: In this study, we established an ensemble computational model for discriminating the near-native docking pose of APKs named "AnkPlex". A dataset of APKs was generated from seven X-ray APKs, which consisted of 3 internal domains, using the reliable docking tool ZDOCK. The dataset was composed of 669 and 44,334 near-native and non-near-native poses, respectively, and it was used to generate eleven informative features. Subsequently, a re-scoring rank was generated by AnkPlex using a combination of a decision tree algorithm and logistic regression. AnkPlex achieved superior efficiency with ≥1 near-native complexes in the 10 top-rankings for nine X-ray complexes compared to ZDOCK, which only obtained six X-ray complexes. In addition, feature analysis demonstrated that the van der Waals feature was the dominant near-native pose out of the potential ankyrin-protein docking poses.

    CONCLUSION: The AnkPlex model achieved a success at predicting near-native docking poses and led to the discovery of informative characteristics that could further improve our understanding of the ankyrin-protein complex. Our computational study could be useful for predicting the near-native poses of binding proteins and desired targets, especially for ankyrin-protein complexes. The AnkPlex web server is freely accessible at http://ankplex.ams.cmu.ac.th .

    Matched MeSH terms: Protein Binding
  6. Probing the interaction of 2,4-dichlorophenoxyacetic acid with human serum albumin as studied by experimental and computational approaches
    Tayyab S, Francis JA, Kabir MZ, Ghani H, Mohamad SB
    Spectrochim Acta A Mol Biomol Spectrosc, 2019 Jan 15;207:284-293.
    PMID: 30267976 DOI: 10.1016/j.saa.2018.09.033
    To characterize the binding of a widely used herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) to the major transporter in human circulation, human serum albumin (HSA), multi-spectroscopic approaches such as fluorescence, absorption and circular dichroism along with computational methods were employed. Analysis of the fluorescence and absorption spectroscopic data confirmed the 2,4-D-HSA complex formation. A static quenching mechanism was evident from the inverse temperature dependence of the KSV values. The complex was stabilized by a weak binding affinity (Ka = 5.08 × 103 M-1 at 298 K). Quantitative analysis of thermodynamic data revealed participation of hydrophobic and van der Waals interactions as well as hydrogen bonds in the binding process. Circular dichroism and three-dimensional fluorescence spectral results showed structural (secondary and tertiary) changes in HSA as well as microenvironmental perturbation around protein fluorophores (Trp and Tyr residues) upon 2,4-D binding. Addition of 2,4-D to HSA was found to improve protein's thermal stability. Competitive displacement results as well as computational analyses suggested preferred location of the 2,4-D binding site as Sudlow's site I (subdomain IIA) in HSA.
    Matched MeSH terms: Protein Binding
  7. Effect of pH on substrate and inhibitor kinetic constants of human liver alanine aminopeptidase. Evidence for two ionizable active center groups
    Garner CW, Behal FJ
    Biochemistry, 1975 Nov 18;14(23):5084-8.
    PMID: 38
    The presence of at least two ionizable active center groups has been detected by a study of the effect of pH upon catalysis of hydrolysis of L-alanyl-beta-naphthylamide by human liver alanine aminopeptidase and upon the inhibition of hydrolysis by inhibitors and substrate analogs. Octanoic acid, octylamine, and peptide inhibitors have been found to be competitive inhibitors and are therefore thought to bind the active center. L-Phe was previously shown to bind the active center since it was found to be a competitive inhibitor of the hydrolysis of tripeptide substrates (Garner, C. W., and Behal, F. J. (1975), Biochemistry 14, 3208). A plot of pKm vs. pH for the substrate L-Ala-beta-naphthylamide showed that binding decreased below pH 5.9 and above 7.5, the points at which the theoretical curve undergoes an integral change in slope. These points are interpreted as the pKa either of substrate ionizable groups or binding-dependent enzyme active center groups. Similar plots of pKm vs. pH for L-alanyl-p-nitroanilide (as substrate) and pKi vs. pH for L-Leu-L-Leu-L-Leu and D-Leu-L-Tyr (as inhibitors) gave pairs fo pKa values of 5.8 and 7.4, 6.0 and 7.5, and 5.7 and 7.5, respectively. All the above substrates (and D-Leu-L-Tyr) have pKa values near 7.5; therefore, the binding-dependent group with a pKa value near 7.5 is possibly this substrate group. Similar plots of pKi vs. pH for the inhibitors L-Phe, L-Met, L-Leu, octylamine, and octanoic acid had only one bending point at 7.7, 7.6, 7.4, 6.3, and 5.9, respectively. Amino acid inhibitors, octylamine, and octanoic acid have no groups with pKa values between 5 and 9. These data indicate that there are two active center ionizable groups with pKa values of approximately 6.0 and 7.5 which are involved in substrate binding or inhibitory amino acid binding but not in catalysis since Vmax was constant at all pH values tested.
    Matched MeSH terms: Protein Binding
  8. Metal substitutions incarbonic anhydrase: a halide ion probe study
    Smith RJ, Bryant RG
    Biochem Biophys Res Commun, 1975 Oct 27;66(4):1281-6.
    PMID: 3
    Matched MeSH terms: Protein Binding
  9. Fulltext Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure
    Sakurama K, Kawai A, Tuan Giam Chuang V, Kanamori Y, Osa M, Taguchi K, et al.
    ACS Omega, 2018 Oct 31;3(10):13790-13797.
    PMID: 30411049 DOI: 10.1021/acsomega.8b02057
    Aripiprazole (ARP), a quinolinone derivative, is an atypical antipsychotic drug that is used in the treatment of schizophrenia. ARP has an extensive distribution and more than 99% of the ARP and dehydro-ARP, the main active metabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In this study, we report on a systematic study of the protein binding of ARP. The interaction of ARP and structurally related compounds with human serum albumin (HSA) was examined using equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and its main metabolite, dehydro-ARP with HSA were found to be significantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectral data indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the binding of these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site II pocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring may control the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of the ARP-HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARP and the sulfur atom of Cys392 in HSA was 3.4-3.6 Å. A similar halogen bond interaction has also been observed in the HSA structure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding of ARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP in various clinical situations and for designing new drugs.
    Matched MeSH terms: Protein Binding
  10. Fulltext Methodological Considerations and Comparisons of Measurement Results for Extracellular Proteolytic Enzyme Activities in Seawater
    Obayashi Y, Wei Bong C, Suzuki S
    Front Microbiol, 2017;8:1952.
    PMID: 29067013 DOI: 10.3389/fmicb.2017.01952
    Microbial extracellular hydrolytic enzymes that degrade organic matter in aquatic ecosystems play key roles in the biogeochemical carbon cycle. To provide linkages between hydrolytic enzyme activities and genomic or metabolomic studies in aquatic environments, reliable measurements are required for many samples at one time. Extracellular proteases are one of the most important classes of enzymes in aquatic microbial ecosystems, and protease activities in seawater are commonly measured using fluorogenic model substrates. Here, we examined several concerns for measurements of extracellular protease activities (aminopeptidases, and trypsin-type, and chymotrypsin-type activities) in seawater. Using a fluorometric microplate reader with low protein binding, 96-well microplates produced reliable enzymatic activity readings, while use of regular polystyrene microplates produced readings that showed significant underestimation, especially for trypsin-type proteases. From the results of kinetic experiments, this underestimation was thought to be attributable to the adsorption of both enzymes and substrates onto the microplate. We also examined solvent type and concentration in the working solution of oligopeptide-analog fluorogenic substrates using dimethyl sulfoxide (DMSO) and 2-methoxyethanol (MTXE). The results showed that both 2% (final concentration of solvent in the mixture of seawater sample and substrate working solution) DMSO and 2% MTXE provide similarly reliable data for most of the tested substrates, except for some substrates which did not dissolve completely in these assay conditions. Sample containers are also important to maintain the level of enzyme activity in natural seawater samples. In a small polypropylene containers (e.g., standard 50-mL centrifugal tube), protease activities in seawater sample rapidly decreased, and it caused underestimation of natural activities, especially for trypsin-type and chymotrypsin-type proteases. In conclusion, the materials and method for measurements should be carefully selected in order to accurately determine the activities of microbial extracellular hydrolytic enzymes in aquatic ecosystems; especially, low protein binding materials should be chosen to use at overall processes of the measurement.
    Matched MeSH terms: Protein Binding
  11. Biomolecular interaction mechanism of an anticancer drug, pazopanib with human serum albumin: a multi-spectroscopic and computational approach
    Kandandapani S, Kabir MZ, Ridzwan NFW, Mohamad SB, Tayyab S
    J Biomol Struct Dyn, 2022 Nov;40(18):8312-8323.
    PMID: 33870854 DOI: 10.1080/07391102.2021.1911850
    Pazopanib (PZP) is a multi-targeting tyrosine kinase inhibitor and is currently approved by FDA for the treatment of soft tissue sarcoma and renal cancer. Molecular interaction mechanism of PZP with human serum albumin (HSA) was explored under simulated physiological conditions (pH = 7.4), using fluorescence and UV absorption spectroscopy along with computational methods. Based on the inverse correlation between the Stern-Volmer constant (Ksv) and temperature, it was concluded that PZP quenched the protein fluorescence through static quenching mechanism. This was also confirmed from the UV-vis absorption spectral results. Moderate binding affinity between PZP and HSA was evident from the Ka values (5.51 - 1.05 × 105 M-1) while PZP-HSA complex formation was driven by hydrophobic and van der Waals interactions as well as hydrogen bonds, as revealed by positive entropy change (ΔS = +98.37 J mol-1 K-1) and negative enthalpy change (ΔH = -60.31 kJ mol-1). Three-dimensional fluorescence spectral results disclosed microenvironmental perturbations around Trp and Tyr residues of the protein upon PZP binding. Interestingly, the addition of PZP to HSA significantly protected the protein against thermal stress. Competitive drug displacement results obtained with warfarin, phenylbutazone and diazepam elucidated Sudlow's Site I, positioned in subdomain IIA of HSA, as the preferred binding site of PZP which was well supported by molecular docking analysis, while molecular dynamics simulation results suggested the stability of the PZP-HSA complex.Communicated by Vsevolod Makeev.
    Matched MeSH terms: Protein Binding
  12. Fulltext Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study
    Al-Thiabat MG, Gazzali AM, Mohtar N, Murugaiyah V, Kamarulzaman EE, Yap BK, et al.
    Molecules, 2021 Aug 31;26(17).
    PMID: 34500740 DOI: 10.3390/molecules26175304
    Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < -15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA-βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9-2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0-100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149-151) compared to FA-FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.
    Matched MeSH terms: Protein Binding
  13. Fulltext Identification and characterisation of thiamine pyrophosphate (TPP) riboswitch in Elaeis guineensis
    Subki A, Ho CL, Ismail NFN, Zainal Abidin AA, Balia Yusof ZN
    PLoS One, 2020;15(7):e0235431.
    PMID: 32726320 DOI: 10.1371/journal.pone.0235431
    The oil palm (Elaeis guineensis) is an important crop in Malaysia but its productivity is hampered by various biotic and abiotic stresses. Recent studies suggest the importance of signalling molecules in plants in coping against stresses, which includes thiamine (vitamin B1). Thiamine is an essential microelement that is synthesized de novo by plants and microorganisms. The active form of thiamine, thiamine pyrophosphate (TPP), plays a prominent role in metabolic activities particularly as an enzymatic cofactor. Recently, thiamine biosynthesis pathways in oil palm have been characterised but the search of novel regulatory element known as riboswitch is yet to be done. Previous studies showed that thiamine biosynthesis pathway is regulated by an RNA element known as riboswitch. Riboswitch binds a small molecule, resulting in a change in production of the proteins encoded by the mRNA. TPP binds specifically to TPP riboswitch to regulate thiamine biosynthesis through a variety of mechanisms found in archaea, bacteria and eukaryotes. This study was carried out to hunt for TPP riboswitch in oil palm thiamine biosynthesis gene. Riboswitch detection software like RiboSW, RibEx, Riboswitch Scanner and Denison Riboswitch Detector were utilised in order to locate putative TPP riboswitch in oil palm ThiC gene sequence that encodes for the first enzyme in the pyrimidine branch of the pathway. The analysis revealed a 192 bp putative TPP riboswitch located at the 3' untranslated region (UTR) of the mRNA. Further comparative gene analysis showed that the 92-nucleotide aptamer region, where the metabolite binds was conserved inter-species. The secondary structure analysis was also carried out using Mfold Web server and it showed a stem-loop structure manifested with stems (P1-P5) with minimum free energy of -12.26 kcal/mol. Besides that, the interaction of riboswitch and its ligand was determined using isothermal titration calorimetry (ITC) and it yielded an exothermic reaction with 1:1 stoichiometry interaction with binding affinities of 0.178 nM, at 30°C. To further evaluate the ability of riboswitch to control the pathway, exogenous thiamine was applied to four months old of oil palm seedlings and sampling of spear leaves tissue was carried out at days 0, 1, 2 and 3 post-treatment for expression analysis of ThiC gene fragment via quantitative polymerase chain reaction (qPCR). Results showed an approximately 5-fold decrease in ThiC gene expression upon application of exogenous thiamine. Quantification of thiamine and its derivatives was carried out via HPLC and the results showed that it was correlated to the down regulation of ThiC gene expression. The application of exogenous thiamine to oil palm affected ThiC gene expression, which supported the prediction of the presence of TPP riboswitch in the gene. Overall, this study provides the first evidence on the presence, binding and the functionality of TPP riboswitch in oil palm. This study is hoped to pave a way for better understanding on the regulation of thiamine biosynthesis pathway in oil palm, which can later be exploited for various purposes especially in manipulation of thiamine biosynthesis pathways in combating stresses in oil palm.
    Matched MeSH terms: Protein Binding
  14. Fulltext Probing the interaction of a therapeutic flavonoid, pinostrobin with human serum albumin: multiple spectroscopic and molecular modeling investigations
    Feroz SR, Mohamad SB, Bakri ZS, Malek SN, Tayyab S
    PLoS One, 2013;8(10):e76067.
    PMID: 24116089 DOI: 10.1371/journal.pone.0076067
    Interaction of a pharmacologically important flavonoid, pinostrobin (PS) with the major transport protein of human blood circulation, human serum albumin (HSA) has been examined using a multitude of spectroscopic techniques and molecular docking studies. Analysis of the fluorescence quenching data showed a moderate binding affinity (1.03 × 10(5) M(-1) at 25°C) between PS and HSA with a 1∶1 stoichiometry. Thermodynamic analysis of the binding data (ΔS = +44.06 J mol(-1) K(-1) and ΔH = -15.48 kJ mol(-1)) and molecular simulation results suggested the involvement of hydrophobic and van der Waals forces, as well as hydrogen bonding in the complex formation. Both secondary and tertiary structural perturbations in HSA were observed upon PS binding, as revealed by intrinsic, synchronous, and three-dimensional fluorescence results. Far-UV circular dichroism data revealed increased thermal stability of the protein upon complexation with PS. Competitive drug displacement results suggested the binding site of PS on HSA as Sudlow's site I, located at subdomain IIA, and was well supported by the molecular modelling data.
    Matched MeSH terms: Protein Binding
  15. Fulltext Identification of Pyrazole Derivatives of Usnic Acid as Novel Inhibitor of SARS-CoV-2 Main Protease Through Virtual Screening Approaches
    Roney M, Singh G, Huq AKMM, Forid MS, Ishak WMBW, Rullah K, et al.
    Mol Biotechnol, 2024 Apr;66(4):696-706.
    PMID: 36752937 DOI: 10.1007/s12033-023-00667-5
    The infection produced by the SARS-CoV-2 virus remains a significant health crisis worldwide. The lack of specific medications for COVID-19 necessitates a concerted effort to find the much-desired therapies for this condition. The main protease (Mpro) of SARS-CoV-2 is a promising target, vital for virus replication and transcription. In this study, fifty pyrazole derivatives were tested for their pharmacokinetics and drugability, resulting in eight hit compounds. Subsequent molecular docking simulations on SARS-CoV-2 main protease afforded two lead compounds with strong affinity at the active site. Additionally, the molecular dynamics (MD) simulations of lead compounds (17 and 39), along with binding free energy calculations, were accomplished to validate the stability of the docked complexes and the binding poses achieved in docking experiments. Based on these findings, compound 17 and 39, with their favorable projected pharmacokinetics and pharmacological characteristics, are the proposed potential antiviral candidates which require further investigation to be used as anti-SARS-CoV-2 medication.
    Matched MeSH terms: Protein Binding
  16. Fulltext Genetic regulation of the yefM-yoeB toxin-antitoxin locus of Streptococcus pneumoniae
    Chan WT, Nieto C, Harikrishna JA, Khoo SK, Othman RY, Espinosa M, et al.
    J Bacteriol, 2011 Sep;193(18):4612-25.
    PMID: 21764929 DOI: 10.1128/JB.05187-11
    Type II (proteic) toxin-antitoxin systems (TAS) are ubiquitous among bacteria. In the chromosome of the pathogenic bacterium Streptococcus pneumoniae, there are at least eight putative TAS, one of them being the yefM-yoeB(Spn) operon studied here. Through footprinting analyses, we showed that purified YefM(Spn) antitoxin and the YefM-YoeB(Spn) TA protein complex bind to a palindrome sequence encompassing the -35 region of the main promoter (P(yefM2)) of the operon. Thus, the locus appeared to be negatively autoregulated with respect to P(yefM2), since YefM(Spn) behaved as a weak repressor with YoeB(Spn) as a corepressor. Interestingly, a BOX element, composed of a single copy (each) of the boxA and boxC subelements, was found upstream of promoter P(yefM2). BOX sequences are pneumococcal, perhaps mobile, genetic elements that have been associated with bacterial processes such as phase variation, virulence regulation, and genetic competence. In the yefM-yoeB(Spn) locus, the boxAC element provided an additional weak promoter, P(yefM1), upstream of P(yefM2) which was not regulated by the TA proteins. In addition, transcriptional fusions with a lacZ reporter gene showed that P(yefM1) was constitutive albeit weaker than P(yefM2). Intriguingly, the coupling of the boxAC element to P(yefM1) and yefM(Spn) in cis (but not in trans) led to transcriptional activation, indicating that the regulation of the yefM-yoeB(Spn) locus differs somewhat from that of other TA loci and may involve as yet unidentified elements. Conservation of the boxAC sequences in all available sequenced genomes of S. pneumoniae which contained the yefM-yoeB(Spn) locus suggested that its presence may provide a selective advantage to the bacterium.
    Matched MeSH terms: Protein Binding
  17. Use of superparamagnetic beads for the isolation of a peptide with specificity to cymbidium mosaic virus
    Ooi DJ, Dzulkurnain A, Othman RY, Lim SH, Harikrishna JA
    J Virol Methods, 2006 Sep;136(1-2):160-5.
    PMID: 16781785
    A modified method for the rapid isolation of specific ligands to whole virus particles is described. Biopanning against cymbidium mosaic virus was carried out with a commercial 12-mer random peptide display library. A solution phase panning method was devised using streptavidin-coated superparamagnetic beads. The solution based panning method was more efficient than conventional immobilized target panning when using whole viral particles of cymbidium mosaic virus as a target. Enzyme-linked immunosorbent assay of cymbidium mosaic virus-binding peptides isolated from the library identified seven peptides with affinity for cymbidium mosaic virus and one peptide which was specific to cymbidium mosaic virus and had no significant binding to odontoglossum ringspot virus. This method should have broad application for the screening of whole viral particles towards the rapid development of diagnostic reagents without the requirement for cloning and expression of single antigens.
    Matched MeSH terms: Protein Binding
  18. Fulltext Engineering receptor-binding domain and heptad repeat domains towards the development of multi-epitopes oral vaccines against SARS-CoV-2 variants
    Arshad NF, Nordin FJ, Foong LC, In LLA, Teo MYM
    PLoS One, 2024;19(8):e0306111.
    PMID: 39146295 DOI: 10.1371/journal.pone.0306111
    The inability of existing vaccines to cope with the mutation rate has highlighted the need for effective preventative strategies for COVID-19. Through the secretion of immunoglobulin A, mucosal delivery of vaccines can effectively stimulate mucosal immunity for better protection against SARS-CoV-2 infection. In this study, various immunoinformatic tools were used to design a multi-epitope oral vaccine against SARS-CoV-2 based on its receptor-binding domain (RBD) and heptad repeat (HR) domains. T and B lymphocyte epitopes were initially predicted from the RBD and HR domains of SARS-CoV-2, and potential antigenic, immunogenic, non-allergenic, and non-toxic epitopes were identified. Epitopes that are highly conserved and have no significant similarity to human proteome were selected. The epitopes were joined with appropriate linkers, and an adjuvant was added to enhance the vaccine efficacy. The vaccine 3D structure constructs were docked with toll-like receptor 4 (TLR-4) and TLR1-TLR2, and the binding affinity was calculated. The designed multi-epitope vaccine construct (MEVC) consisted of 33 antigenic T and B lymphocyte epitopes. The results of molecular dockings and free binding energies confirmed that the MEVC effectively binds to TLR molecules, and the complexes were stable. The results suggested that the designed MEVC is a potentially safe and effective oral vaccine against SARS-CoV-2. This in silico study presents a novel approach for creating an oral multi-epitope vaccine against the rapidly evolving SARS-CoV-2 variants. These findings offer valuable insights for developing an effective strategy to combat COVID-19. Further preclinical and clinical studies are required to confirm the efficacy of the MEVC vaccine.
    Matched MeSH terms: Protein Binding
  19. Isolation of phenolic compound from Lawsonia inermis and its prediction as anti-diabetic agent using molecular docking and molecular dynamic simulation
    Musfiroh I, Ifaya M, Sahidin I, Herawati DMD, Tjitraresmi A, Abdurrahman S, et al.
    J Biomol Struct Dyn, 2024;42(21):11415-11424.
    PMID: 37776010 DOI: 10.1080/07391102.2023.2262595
    High blood sugar is a defining feature of chronic disease, diabetes mellitus (DM). There are numerous commercially available medications for the treatment of DM. However, managing the patient's glucose levels remain a challenge because of the gradual reduction in beta-cell function and some side effects from the long-term use of various medications. Previous research has shown that the phenolic compound of henna plant (Lawsonia inermis L.) has the potential as anti-diabetic agent since it is able to suppress the digesting of α-amylase enzyme. In these studies, the plant' phenolic compounds have been isolated and characterized using UV, IR, NMR and LC-MS methods. Furthermore, the compound interaction into the active site of the α-amylase enzyme has been analyzed using molecular docking and molecular dynamics, as well as into α-glucosidase enzyme for predicting of the affinities. The results showed that isolated compound has the molecular formula of C15H10O6 with eleven degrees of unsaturation (DBE; double bond equivalence). The DBE value corresponds to the structure of the luteolin compound having an aromatic ring (8), a carbonyl group on the side chain (1) and a ketone ring with (2). The interaction study of the isolated compound with α-amylase and α-glucosidase enzyme using molecular docking compared to the positive control (acarbose) gave binding energy of -8.03 and -8.95 kcal/mol, respectively. The molecular dynamics simulation using the MM-PBSA method, complex stability based on solvent accessible surface area (SASA), root mean square deviation (RMSD), and root mean square fluctuation (RMSF) revealed that the compound has a high affinity for receptors. The characteristics of skin permeability, absorption, and distribution using ADME-Tox model were also well predicted. The results indicate that the phenolic compound isolated from L. inermis leaf was luteolin and it has the potential as an anti-diabetic agent.Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Protein Binding
  20. Why is binding of a divalent metal cation to a structural motif containing four carboxylate residues not accompanied by a conformational change?
    Lushchekina S, Weiner L, Ashani Y, Emrizal R, Firdaus-Raih M, Silman I, et al.
    Protein Sci, 2024 Dec;33(12):e5206.
    PMID: 39548604 DOI: 10.1002/pro.5206
    We earlier showed that Torpedo californica acetylcholinesterase (AChE) contains a cluster of four conserved aspartates that can strongly bind divalent cations, which we named the 4D motif. Binding of the divalent metal cations greatly increases its thermal stability. Here we systematically examined all available crystallographic structures of T. californica AChE. Two additional metal-binding sites were identified, both composed of acidic and histidine residues. Relative binding to the 4D and additional sites was studied using metadynamics simulations. It was observed that in crystal structures devoid of metal ions in the 4D site, the conformation of T. californica AChE is almost identical to that in structures in which it is occupied by a divalent metal ion. Closer examination of the 4D motif reveals that three of the four acidic residues form ion pairs with conserved basic residues surrounding them. We named this new motif the 4A/3B motif. Molecular dynamics with quantum potential simulations was used to quantify the 4D motif's binding strength compared with that of the metal-binding site in the protein fXIIIa, which consists of four aspartates, but is devoid of adjacent cationic residues. Whereas fXIIIa's 4D site, in the absence of a metal cation, expanded significantly in the simulation, that of Torpedo AChE displayed only minor periodic changes in size. Furthermore, the energy of metal ion unbinding from the two sites differs by ca. 10 kcal/mol. We identified several other proteins in the PDB that contain the 4A/3B motif, whose conformations are identical in the presence or absence of a metal ion. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at https://proteopedia.org/w/Journal:Protein_Science:4.
    Matched MeSH terms: Protein Binding
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