Displaying publications 1 - 20 of 302 in total

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  1. Serum albumin: clinical significance of drug binding and development as drug delivery vehicle
    Tayyab S, Feroz SR
    Adv Protein Chem Struct Biol, 2021;123:193-218.
    PMID: 33485484 DOI: 10.1016/bs.apcsb.2020.08.003
    Human serum albumin, the primary transport and reservoir protein in the human circulatory system, interacts with numerous endogenous and exogenous ligands of varying structural characteristics. The mode of binding of drugs to albumin is central to understanding their pharmacokinetic profiles and has a major influence on their in vivo efficacy. Altered drug binding to albumin due to drug-drug interactions or abnormal physiology may result in marked changes in the active drug concentration, thus affecting its pharmacokinetic and pharmacodynamic properties. The propensity of drug-drug interaction to be clinically significant as well as possible exploitation of such interactions for therapeutic purposes is reviewed. Being the major organs of albumin metabolism, any impairment in the liver and kidney functions frequently alter the level of serum albumin, which affects the pharmacokinetic profiles of drugs and may have serious clinical implications. The natural function of serum albumin as a drug carrier is facilitated by its interaction with various cellular receptors. These receptors not only promote the uptake of drugs into cells but are also responsible for the extraordinarily long circulatory half-life of albumin. This property in combination with the presence of multiple ligand binding pockets have led to the emergence of serum albumin as an attractive vehicle for novel drug delivery systems. Here, we provide an overview of various albumin-based drug delivery strategies, classified according to their methods of drug attachment, and highlight their experimental and clinical successes.
    Matched MeSH terms: Protein Binding
  2. Application of machine learning on understanding biomolecule interactions in cellular machinery
    Dixit R, Khambhati K, Supraja KV, Singh V, Lederer F, Show PL, et al.
    Bioresour Technol, 2023 Feb;370:128522.
    PMID: 36565819 DOI: 10.1016/j.biortech.2022.128522
    Machine learning (ML) applications have become ubiquitous in all fields of research including protein science and engineering. Apart from protein structure and mutation prediction, scientists are focusing on knowledge gaps with respect to the molecular mechanisms involved in protein binding and interactions with other components in the experimental setups or the human body. Researchers are working on several wet-lab techniques and generating data for a better understanding of concepts and mechanics involved. The information like biomolecular structure, binding affinities, structure fluctuations and movements are enormous which can be handled and analyzed by ML. Therefore, this review highlights the significance of ML in understanding the biomolecular interactions while assisting in various fields of research such as drug discovery, nanomedicine, nanotoxicity and material science. Hence, the way ahead would be to force hand-in hand of laboratory work and computational techniques.
    Matched MeSH terms: Protein Binding
  3. Leveraging binding pose metadynamics to optimise target fishing predictions for three diverse ligands and their true targets
    Yau MQ, Wan AJ, Tiong ASH, Yiap YS, Loo JSE
    Chem Biol Drug Des, 2024 Jul;104(1):e14591.
    PMID: 39010276 DOI: 10.1111/cbdd.14591
    Computational target fishing plays an important role in target identification, particularly in drug discovery campaigns utilizing phenotypic screening. Numerous approaches exist to predict potential targets for a given ligand, but true targets may be inconsistently ranked. More advanced simulation methods may provide benefit in such cases by reranking these initial predictions. We evaluated the ability of binding pose metadynamics to improve the predicted rankings for three diverse ligands and their six true targets. Initial predictions using pharmacophore mapping showed no true targets ranked in the top 50 and two targets each ranked within the 50-100, 100-150, and 250-300 ranges respectively. Following binding pose metadynamics, ranking of true targets improved for four out of the six targets and included the highest ranked predictions overall, while rankings deteriorated for two targets. The revised rankings predicted two true targets ranked within the top 50, and one target each within the 50-100, 100-150, 150-200, and 200-250 ranges respectively. The findings of this study demonstrate that binding pose metadynamics may be of benefit in refining initial predictions from structure-based target fishing algorithms, thereby improving the efficiency of the target identification process in drug discovery efforts.
    Matched MeSH terms: Protein Binding*
  4. Fulltext Evaluation of the binding interactions between Plasmodium falciparum Kelch-13 mutant recombinant proteins with artemisinin
    Md Yusuf N, Azman AN, Abdul Aziz AA, Ahmad Fuad FA, Nasarudin RN, Hisam S
    PLoS One, 2024;19(8):e0306975.
    PMID: 39146276 DOI: 10.1371/journal.pone.0306975
    Malaria, an ancient mosquito-borne illness caused by Plasmodium parasites, is mostly treated with Artemisinin Combination Therapy (ACT). However, Single Nucleotide Polymorphisms (SNPs) mutations in the P. falciparum Kelch 13 (PfK13) protein have been associated with artemisinin resistance (ART-R). Therefore, this study aims to generate PfK13 recombinant proteins incorporating of two specific SNPs mutations, PfK13-V494I and PfK13-N537I, and subsequently analyze their binding interactions with artemisinin (ART). The recombinant proteins of PfK13 mutations and the Wild Type (WT) variant were expressed utilizing a standard protein expression protocol with modifications and subsequently purified via IMAC and confirmed with SDS-PAGE analysis and Orbitrap tandem mass spectrometry. The binding interactions between PfK13-V494I and PfK13-N537I propeller domain proteins ART were assessed through Isothermal Titration Calorimetry (ITC) and subsequently validated using fluorescence spectrometry. The protein concentrations obtained were 0.3 mg/ml for PfK13-WT, 0.18 mg/ml for PfK13-V494I, and 0.28 mg/ml for PfK13-N537I. Results obtained for binding interaction revealed an increased fluorescence intensity in the mutants PfK13-N537I (83 a.u.) and PfK13-V494I (143 a.u.) compared to PfK13-WT (33 a.u.), indicating increased exposure of surface proteins because of the looser binding between PfK13 protein mutants with ART. This shows that the PfK13 mutations may induce alterations in the binding interaction with ART, potentially leading to reduced effectiveness of ART and ultimately contributing to ART-R. However, this study only elucidated one facet of the contributing factors that could serve as potential indicators for ART-R and further investigation should be pursued in the future to comprehensively explore this complex mechanism of ART-R.
    Matched MeSH terms: Protein Binding*
  5. A critical view on the analysis of fluorescence quenching data for determining ligand-protein binding affinity
    Bakar KA, Feroz SR
    Spectrochim Acta A Mol Biomol Spectrosc, 2019 Dec 05;223:117337.
    PMID: 31302564 DOI: 10.1016/j.saa.2019.117337
    The past decade has seen an increase in the number of research papers on ligand binding to proteins based on fluorescence spectroscopy. In most cases, determination of the binding affinity is made by analyzing the quenching of protein fluorescence induced by the ligand. However, many such articles, even those published in reputed journals, suffer from several mistakes with regard to analysis of fluorescence quenching data. Using the binding of phenylbutazone to human serum albumin as a model, we consider some of these mistakes and show how they affect the values of the association constant. In particular, the failure to correct for the inner filter effect and the use of unsuitable equations are discussed. Ligand binding data presented in these articles should be treated with caution, especially in the absence of data from complementary techniques.
    Matched MeSH terms: Protein Binding
  6. Structural and functional characterization of Solanum lycopersicum phosphatidylinositol 3-kinase C2 domain
    Pak Dek MS, Padmanabhan P, Tiwari K, Todd JF, Paliyath G
    Plant Physiol Biochem, 2020 Mar;148:180-192.
    PMID: 31972387 DOI: 10.1016/j.plaphy.2020.01.014
    Phosphatidylinositol 3-kinases (PI3Ks) are characterized by the presence of a C2 domain at the N-terminal end (class I, III); or at both the N-terminal and C-terminal ends (class II), sometimes including a Plextrin homology domain and/or a Ras domain. Plant PI3Ks are analogous to the class III mammalian PI3K. An N-terminal fragment (~170 aa) of the tomato PI3K regulatory domain including the C2 domain, was cloned and expressed in a bacterial system. This protein was purified to homogeneity and its physicochemical properties analyzed. The purified protein showed strong binding with monophosphorylated phosphatidylinositols, and the binding was dependent on calcium ion concentration and pH. In the overall tertiary structure of PI3K, C2 domain showed unique characteristics, having three antiparallel beta-sheets, hydrophobic regions, acidic as well as alkaline motifs, that can enable its membrane binding upon activation. To elucidate the functional significance of C2 domain, transgenic tobacco plants expressing the C2 domain of PI3K were generated. Transgenic plants showed defective pollen development and disrupted seed set. Flowers from the PI3K-C2 transgenic plants showed delayed wilting, and a decrease in ethylene production. It is likely that introduction of the PI3K-C2 segment may have interfered with the normal binding of PI3K to the membrane, delaying the onset of membrane lipid catabolism that lead to senescence.
    Matched MeSH terms: Protein Binding
  7. An experimental and theoretical study on the interaction of DNA and BSA with novel Ni2+, Cu2+ and VO2+ complexes derived from vanillin bidentate Schiff base ligand
    Dostani M, Kianfar AH, Mahmood WA, Dinari M, Farrokhpour H, Sabzalian MR, et al.
    Spectrochim Acta A Mol Biomol Spectrosc, 2017 Jun 05;180:144-153.
    PMID: 28284160 DOI: 10.1016/j.saa.2017.02.047
    In this investigation, the structure of bidentate N,N-Schiff base ligand of vanillin, (E)-4-(((2-amino-5-nitrophenyl)imino)methyl)-2-methoxyphenol (HL) was determined by single crystal X-ray diffraction. The interaction of new [CuL2], [NiL2] and [VOL2] complexes with DNA and BSA was explored through UV-Vis and fluorescence spectroscopy. The electronic spectra changes displayed an isosbestic point for the complexes upon titration with DNA. The Kb values for the complexes [CuL2], [NiL2] and [VOL2] were 2.4×105, 1.9×105 and 4.2×104, respectively. [CuL2] complex was bound more toughly than [NiL2] and [VOL2] complexes. These complexes had a significant interaction with Bovine Serum Albumin (BSA) and the results demonstrated that the quenching mechanism was a static procedure. Also, the complexes interacted with BSA by more than one binding site (n>1). Finally, the theoretical studies were performed using the docking method to calculate the binding constants and recognize the binding site of the DNA and BSA with the complexes. The ligand and complexes including Ni2+, Cu2+ and VO2+ ions were colonized by fungal growth.
    Matched MeSH terms: Protein Binding
  8. Fulltext Dimeric Ankyrin with Inverted Module Promotes Bifunctional Property in Capturing Capsid to Impede HIV-1 Replication
    Juntit OA, Sornsuwan K, Wisitponchai T, Sanghiran Lee V, Sakkhachornphop S, Yasamut U, et al.
    Int J Mol Sci, 2023 Mar 09;24(6).
    PMID: 36982337 DOI: 10.3390/ijms24065266
    Several anti-HIV scaffolds have been proposed as complementary treatments to highly active antiretroviral therapy. AnkGAG1D4, a designed ankyrin repeat protein, formerly demonstrated anti-HIV-1 replication by interfering with HIV-1 Gag polymerization. However, the improvement of the effectiveness was considered. Recently, the dimeric molecules of AnkGAG1D4 were accomplished in enhancing the binding activity against HIV-1 capsid (CAp24). In this study, the interaction of CAp24 against the dimer conformations was elucidated to elaborate the bifunctional property. The accessibility of the ankyrin binding domains was inspected by bio-layer interferometry. By inverting the second module of dimeric ankyrin (AnkGAG1D4NC-CN), the CAp24 interaction KD was significantly reduced. This reflects the capability of AnkGAG1D4NC-CN in simultaneously capturing CAp24. On the contrary, the binding activity of dimeric AnkGAG1D4NC-NC was indistinguishable from the monomeric AnkGAG1D4. The bifunctional property of AnkGAG1D4NC-CN was subsequently confirmed in the secondary reaction with additional p17p24. This data correlates with the MD simulation, which suggested the flexibility of the AnkGAG1D4NC-CN structure. The CAp24 capturing capacity was influenced by the distance of the AnkGAG1D4 binding domains to introduce the avidity mode of AnkGAG1D4NC-CN. Consequently, AnkGAG1D4NC-CN showed superior potency in interfering with HIV-1 NL4-3 WT and HIV-1 NL4-3 MIRCAI201V replication than AnkGAG1D4NC-NC and an affinity improved AnkGAG1D4-S45Y.
    Matched MeSH terms: Protein Binding
  9. Fulltext Molecular Dynamics Simulations Reveal Novel Interacting Regions of Human Prion Protein to Brucella abortus Hsp60 Protein
    Le-Dao HA, Dinh TT, Tran TL, Lee VS, Tran-Van H
    Mol Biotechnol, 2024 Apr;66(4):687-695.
    PMID: 36633832 DOI: 10.1007/s12033-023-00655-9
    The distinctive morphology characteristics of microfold cells (M cells) allow the vaccine antigen not only to interact with immune cells directly, but also to effectively stimulate mucosal immune responses via receptors on its apical surface. Human prion protein, a transmembrane receptor for Brucella abortus Hsp60, is highly expressed on the M cell surface. Nonetheless, this protein tends to express in inclusion body in prokaryotic hosts. In this study, the shorter interacting regions of human prion protein were identified via computational methods such as docking and molecular dynamics simulations to minimize its aggregation tendency. The computational calculations revealed three novel human prion protein-interacting regions, namely PrP125, PrP174, and PrP180. In accordance with in silico prediction, the biologically synthesized peptides fusing with GST tag demonstrated their specific binding to Hsp60 protein via pull-down assay. Hence, this finding laid the groundwork for M-cell targeting candidate validation through these newly identified interacting regions.
    Matched MeSH terms: Protein Binding
  10. Fulltext Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study
    Khan A, Hussain S, Ahmad S, Suleman M, Bukhari I, Khan T, et al.
    Comput Biol Med, 2022 Feb;141:105163.
    PMID: 34979405 DOI: 10.1016/j.compbiomed.2021.105163
    The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?
    Matched MeSH terms: Protein Binding
  11. Peptidyl-prolyl isomerases: functionality and potential therapeutic targets in cardiovascular disease
    Rostam MA, Piva TJ, Rezaei HB, Kamato D, Little PJ, Zheng W, et al.
    Clin Exp Pharmacol Physiol, 2015 Feb;42(2):117-24.
    PMID: 25377120 DOI: 10.1111/1440-1681.12335
    Peptidyl-prolyl cis/trans isomerases (PPIases) are a conserved group of enzymes that catalyse the conversion between cis and trans conformations of proline imidic peptide bonds. These enzymes play critical roles in regulatory mechanisms of cellular function and pathophysiology of disease. There are three different classes of PPIases and increasing interest in the development of specific PPIase inhibitors. Cyclosporine A, FK506, rapamycin and juglone are known PPIase inhibitors. Herein, we review recent advances in elucidating the role and regulation of the PPIase family in vascular disease. We focus on peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an important member of the PPIase family that plays a role in cell cycle progression, gene expression, cell signalling and cell proliferation. In addition, Pin1 may be involved in atherosclerosis. The unique role of Pin1 as a molecular switch that impacts on multiple downstream pathways necessitates the evaluation of a highly specific Pin1 inhibitor to aid in potential therapeutic drug discovery.
    Matched MeSH terms: Protein Binding/physiology
  12. In silico screening of Allium cepa phytochemicals for their binding abilities to SARS and SARS-CoV-2 3C-like protease and COVID-19 human receptor ACE-2
    Bondhon TA, Fatima A, Jannat K, Hasan A, Jahan R, Nissapatorn V, et al.
    Trop Biomed, 2021 Jun 01;38(2):214-221.
    PMID: 34172713 DOI: 10.47665/tb.38.2.060
    Corona virus SARS-CoV-2-induced viral disease (COVID-19) is a zoonotic disease that was initially transmitted from animals to humans. The virus surfaced towards the end of December 2019 in Wuhan, China where earlier SARS (Severe Acute Respiratory Syndrome) had also surfaced in 2003. Unlike SARS, SARS-CoV-2 (a close relative of the SARS virus) created a pandemic, and as of February 24 2021, caused 112,778,672 infections and 2,499,252 deaths world-wide. Despite the best efforts of scientists, no drugs against COVID-19 are yet in sight; five vaccines have received emergency approval in various countries, but it would be a difficult task to vaccinate twice the world population of 8 billion. The objective of the present study was to evaluate through in silico screening a number of phytochemicals in Allium cepa (onion) regarding their ability to bind to the main protease of COVID-19 known as the 3C-like protease or 3CLpro, (PDB ID: 6LU7), 3CLpro of SARS (PDB ID: 3M3V), and human angiotensin converting enzyme-2 (ACE-2), [PDB ID: 1R42], which functions as a receptor for entry of the virus into humans. Molecular docking (blind docking, that is docking not only against any target pocket) were done with the help of AutoDockVina. It was observed that of the twenty-two phytochemicals screened, twelve showed good binding affinities to the main protease of SARS-CoV-2. Surprisingly, the compounds also demonstrated good binding affinities to ACE-2. It is therefore very likely that the binding affinities shown by these compounds against both 3CLpro and ACE-2 merit further study for their potential use as therapeutic agents.
    Matched MeSH terms: Protein Binding/drug effects
  13. Fulltext Development of flexible electrochemical impedance spectroscopy-based biosensing platform for rapid screening of SARS-CoV-2 inhibitors
    Kiew LV, Chang CY, Huang SY, Wang PW, Heh CH, Liu CT, et al.
    Biosens Bioelectron, 2021 Jul 01;183:113213.
    PMID: 33857754 DOI: 10.1016/j.bios.2021.113213
    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the cells through the binding of its spike protein (S-protein) to the cell surface-expressing angiotensin-converting enzyme 2 (ACE2). Thus, inhibition of S-protein-ACE2 binding may impede SARS-CoV-2 cell entry and attenuate the progression of Coronavirus disease 2019 (COVID-19). In this study, an electrochemical impedance spectroscopy-based biosensing platform consisting of a recombinant ACE2-coated palladium nano-thin-film electrode as the core sensing element was fabricated for the screening of potential inhibitors against S-protein-ACE2 binding. The platform could detect interference of small analytes against S-protein-ACE2 binding at low analyte concentration and small volume (0.1 μg/mL and ~1 μL, estimated total analyte consumption protein-ACE2 binding were identified. This includes (2S,3aS,6aS)-1-((S)-N-((S)-1-Carboxy-3-phenylpropyl)alanyl)tetrahydrocyclopenta[b] pyrrole-2-carboxylic acid (ramiprilat) and (2S,3aS,7aS)-1-[(2S)-2-[[(2S)-1-Carboxybutyl]amino]propanoyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carboxylic acid (perindoprilat) that reduced the binding affinity of S-protein to ACE2 by 72% and 67%; and SARS-CoV-2 in vitro infectivity to the ACE2-expressing human oral cavity squamous carcinoma cells (OEC-M1) by 36.4 and 20.1%, respectively, compared to the PBS control. These findings demonstrated the usefulness of the developed biosensing platform for the rapid screening of modulators for S-protein-ACE2 binding.
    Matched MeSH terms: Protein Binding
  14. Characterization of Climbazole-Bovine serum albumin interaction by experimental and in silico approaches
    Zahirul Kabir M, Tayyab H, Erkmen C, Kurbanoglu S, Mohamad SB, Uslu B
    Spectrochim Acta A Mol Biomol Spectrosc, 2023 Mar 05;288:122197.
    PMID: 36470090 DOI: 10.1016/j.saa.2022.122197
    Interactive association of an antifungal drug, climbazole (CBZ) with the carrier protein in bovine circulation, bovine serum albumin (BSA) was explored by fluorescence and absorption spectroscopy along with in silico techniques. The fluorescence and absorption spectral alterations of the protein upon addition of CBZ affirmed the complex foration between CBZ and BSA. The inverse temperature dependence behaviour of the KSV values as well as the hyperchromic result of the protein's absorption signals characterized CBZ-triggered quenching of BSA fluorescence as the static quenching. A weak binding affinity (Ka = 3.12-1.90-× 103 M-1) was reported towards the CBZ-BSA association process. Interpretation of thermodynamic data (entropy change = +14.68 J mol-1 K-1 and enthalpy change = -15.07 kJ mol-1) and in silico analyses anticipated that hydrophobic forces, van der Waals forces and hydrogen bonds were the key intermolecular forces in the complex stabilization. Inclusion of CBZ to BSA produced microenvironmental perturbations around Tyr and Trp residues, and also significantly defended temperature-induced destabilization of BSA. The binding locus of CBZ was detected in the proximity of Sudlow's sites I (subdomain IIA) and II (subdomain IIIA) of BSA, exhibiting greater preference towards site II, as revealed by competitive site-marker displacement investigations and in silico analysis. The stability of the CBZ-BSA complex was further validated by the molecular dynamics simulation assessments.
    Matched MeSH terms: Protein Binding
  15. Interaction mechanism of a cysteine protease inhibitor, odanacatib, with human serum albumin: In vitro and bioinformatics studies
    Asngari NJM, Bakar KA, Feroz SR, Razak FA, Halim AAA
    Biophys Chem, 2024 Feb;305:107140.
    PMID: 38118338 DOI: 10.1016/j.bpc.2023.107140
    Odanacatib (ODN) is a selective cathepsin K inhibitor that acts as an anti-resorptive agent to treat osteoporosis. ODN is also found effective in reducing the effect of severe periodontitis. The interaction between ODN and human serum albumin (HSA) was investigated using spectroscopic, microscopic, and in silico approaches to characterize their binding. The fluorescence intensity of HSA increased upon the addition of increasing concentrations of ODN accompanied by blueshift in the fluorescence spectrum, which suggested hydrophobic formation around the microenvironment of the fluorophores upon ODN binding. A moderate binding affinity was obtained for ODN-HSA binding, with binding constant (Ka) values of ∼104 M-1. Circular dichroism results suggested that the overall secondary and tertiary structures of HSA were both only slightly altered upon ODN binding. The surface morphology of HSA was also affected upon ODN binding, showing aggregate formation. Drug displacement and molecular docking results revealed that ODN preferably binds to site III in subdomain IB of HSA, while molecular dynamics simulations indicated formation of a stable protein complex when site III was occupied by ODN. The ODN-HSA complex was mainly stabilized by a combination of hydrogen bonding, hydrophobic interactions, and van der Waals forces. These findings provide additional information to understand the interaction mechanism of ODN in blood circulation and may help in future improvements on the adverse effects of ODN.
    Matched MeSH terms: Protein Binding
  16. Deciphering the binding mode and structural perturbations in floxuridine-human serum albumin complexation with spectroscopic, microscopic, and computational techniques
    Rehman F, Abubakar M, Ridzwan NFW, Mohamad SB, Abd Halim AA, Tayyab S
    Spectrochim Acta A Mol Biomol Spectrosc, 2024 Mar 05;308:123641.
    PMID: 38061108 DOI: 10.1016/j.saa.2023.123641
    The binding mode of antineoplastic antimetabolite, floxuridine (FUDR), with human serum albumin (HSA), the leading carrier in blood circulation, was ascertained using multi-spectroscopic, microscopic, and computational techniques. A static fluorescence quenching was established due to decreased Ksv values with rising temperatures, suggesting FUDR-HSA complexation. UV-vis absorption spectral results also supported this conclusion. The binding constant, Ka values, were found within 9.7-7.9 × 103 M-1 at 290, 300, and 310 K, demonstrating a moderate binding affinity for the FUDR-HSA system. Thermodynamic data (ΔS = +46.35 J.mol-1.K-1 and ΔH = -8.77 kJ.mol-1) predicted the nature of stabilizing forces (hydrogen-bonds, hydrophobic, and van der Waals interactions) for the FUDR-HSA complex. Circular dichroism spectra displayed a minor disruption in the protein's 2° and 3° structures. At the same time, atomic force microscopy images proved variations in the FUDR-HSA surface morphology, confirming its complex formation. The protein's microenvironment around Trp/Tyr residues was also modified, as judged by 3-D fluorescence spectra. FUDR-bound HSA showed better resistance against thermal stress. As disclosed from ligand displacement studies, the FUDR binding site was placed in subdomain IIA (Site I). Further, the molecular docking analysis corroborated the competing displacement studies. Molecular dynamics evaluations revealed that the complex achieved equilibrium during simulations, confirming the FUDR-HSA complex's stability.
    Matched MeSH terms: Protein Binding
  17. Fulltext An in vitro potency assay using nicotinic acetylcholine receptor binding works well with antivenoms against Bungarus candidus and Naja naja
    Ratanabanangkoon K, Simsiriwong P, Pruksaphon K, Tan KY, Chantrathonkul B, Eursakun S, et al.
    Sci Rep, 2018 06 26;8(1):9716.
    PMID: 29946111 DOI: 10.1038/s41598-018-27794-3
    In order to facilitate/expedite the production of effective and affordable snake antivenoms, a novel in vitro potency assay was previously developed. The assay is based on an antiserum's ability to bind to postsynaptic neurotoxin (PSNT) and thereby inhibit the PSNT binding to the nicotinic acetylcholine receptor (nAChR). The assay was shown to work well with antiserum against Thai Naja kaouthia which produces predominantly the lethal PSNTs. In this work, the assay is demonstrated to work well with antiserum/antivenom against Bungarus candidus (BC), which also produces lethal presynaptic neurotoxins, as well as antivenom against Sri Lankan Naja naja (NN), which produces an abundance of cytotoxins. The in vitro and in vivo median effective ratios (ER50s) for various batches of antisera against BC showed a correlation (R2) of 0.8922 (p 
    Matched MeSH terms: Protein Binding
  18. In silico assessment of dehalogenase from Bacillus thuringiensis H2 in relation to its salinity-stability and pollutants degradation
    Oyewusi HA, Huyop F, Wahab RA, Hamid AAA
    J Biomol Struct Dyn, 2022;40(19):9332-9346.
    PMID: 34014147 DOI: 10.1080/07391102.2021.1927846
    Increased scientific interest has led to the rise in biotechnological uses of halophilic and halotolerant microbes for hypersaline wastewater bioremediation. Hence, this study performed molecular docking, molecular dynamic (MD) simulations, and validation by Molecular Mechanic Poisson-Boltzmann Surface Area (MM-PBSA) calculations on the DehH2 from Bacillus thuringiensis H2. We aimed to identify the interactions of DehH2 with substrates haloacids, haloacetates, and chlorpyrifos under extreme salinity (35% NaCl). MD simulations revealed that DehH2 preferentially degraded haloacids and haloacetates (-6.3 to -4.7 kcal/mol) by forming three or four hydrogen bonds to the catalytic triad, Asp125, Arg201, and Lys202. Conversely, chlorpyrifos was the least preferred substrate in both MD simulations and MM-PBSA calculations. MD simulation results ranked the DehH2-L-2CP complex (RMSD □0.125-0.23 nm) as the most stable while the least was the DehH2-chlorpyrifos complex (RMSD 0.32 nm; RMSF 0.0 - 0.29). The order of stability was as follows: DehH2-L-2CP > DehH2-MCA > DehH2-D-2CP > DehH2-3CP > DehH2-2,2-DCP > DehH2-2,3-DCP > DehH2-TCA > DehH2-chlorpyrifos. The MM-PBSA calculations further affirmed the DehH2-L-2CP complex's highest stability with the lowest binding energy of -45.14 kcal/mol, followed closely by DehH2-MCA (-41.21 kcal/mol), DehH2-D-2CP (-31.59 kcal/mol), DehH2-3CP (-30.75 kcal/mol), DehH2-2,2- DCP (-29.72 kcal/mol), DehH2-2,3-DCP (-22.20 kcal/mol) and DehH2-TCA (-18.46 kcal/mol). The positive binding energy of the DehH2-chlorpyrifos complex (+180.57 kcal/mol) proved the enzyme's non-preference for the substrate. The results ultimately illustrated the unique specificity of the DehH2 to degrade the above-said pollutants under a hypersaline condition.Communicated by Ramaswamy H. Sarma.
    Matched MeSH terms: Protein Binding
  19. Use of computational and wet lab techniques to examine the molecular association between a potent hepatitis C virus inhibitor, PSI-6206 and human serum albumin
    Abubakar M, Mohamed SB, Abd Halim AA, Tayyab S
    Spectrochim Acta A Mol Biomol Spectrosc, 2023 Jun 05;294:122543.
    PMID: 36868020 DOI: 10.1016/j.saa.2023.122543
    This study explores the plausible molecular interaction between a potent hepatitis C virus inhibitor, PSI-6206 (PSI), and human serum albumin (HSA), a primary transporter in blood plasma. Results obtained from both computational viz. molecular docking and molecular dynamics (MD) simulation and wet lab techniques such as UV absorption, fluorescence, circular dichroism (CD), and atomic force microscopy (AFM) complemented each other. While docking results identified PSI binding to subdomain IIA (Site I) of HSA by forming six hydrogen bonds, MD simulations signified the complex stability throughout the 50,000 ps. A consistent cutback in the Stern-Volmer quenching constant (Ksv) along with rising temperatures supported the static mode of fluorescence quenching in response to PSI addition and implied the development of the PSI-HSA complex. This discovery was backed by the alteration of the HSA UV absorption spectrum, a larger value (>1010 M-1.s-1) of the bimolecular quenching rate constant (kq) and the AFM-guided swelling of the HSA molecule, in the presence of PSI. Moreover, the fluorescence titration results revealed a modest binding affinity (4.27-6.25×103 M-1) in the PSI-HSA system, involving hydrogen bonds, van der Waals and hydrophobic interactions, as inferred from ΔS = + 22.77 J mol-1 K-1 and ΔH = - 11.02 KJ mol-1values. CD and 3D fluorescence spectra reminded significant adjustment in the 2° and 3° structures and modification in the Tyr/Trp microenvironment of the protein in the PSI-bound state. The results obtained from drug competing experiments also advocated the binding location of PSI in HSA as Site I.
    Matched MeSH terms: Protein Binding
  20. In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing
    Mohamed EAR, Abdel-Rahman IM, Zaki MEA, Al-Khdhairawi A, Abdelhamid MM, Alqaisi AM, et al.
    J Mol Model, 2023 Feb 20;29(3):70.
    PMID: 36808314 DOI: 10.1007/s00894-023-05457-z
    BACKGROUND: In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.

    METHODS: As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.

    RESULTS: The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

    Matched MeSH terms: Protein Binding
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