Displaying publications 161 - 180 of 256 in total

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  1. Docking of noncompetitive inhibitors into dengue virus type 2 protease: understanding the interactions with allosteric binding sites
    Othman R, Kiat TS, Khalid N, Yusof R, Newhouse EI, Newhouse JS, et al.
    J Chem Inf Model, 2008 Aug;48(8):1582-91.
    PMID: 18656912 DOI: 10.1021/ci700388k
    A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.
    Matched MeSH terms: Ligands
  2. Fulltext Green Biosynthesis, Antioxidant, Antibacterial, and Anticancer Activities of Silver Nanoparticles of Luffa acutangula Leaf Extract
    Nallappan D, Fauzi AN, Krishna BS, Kumar BP, Reddy AVK, Syed T, et al.
    Biomed Res Int, 2021;2021:5125681.
    PMID: 34631882 DOI: 10.1155/2021/5125681
    Studies on green biosynthesis of newly engineered nanoparticles for their prominent medicinal applications are being the torch-bearing concerns of the state-of-the-art research strategies. In this concern, we have engineered the biosynthesized Luffa acutangula silver nanoparticles of flavonoid O-glycosides in the anisotropic form isolated from aqueous leave extracts of Luffa acutangula, a popular traditional and ayurvedic plant in south-east Asian countries. These were structurally confirmed by Ultraviolet-visible (UV-Vis), Fourier transform infrared spectroscopy accessed with attenuated total reflection (FTIR-ATR) spectral analyses followed by the scanning electron microscopic (SEM) and the X-ray diffraction (XRD) crystallographic studies and found them with the face-centered cubic (fcc) structure. Medicinally, we have explored their significant antioxidant (DPPH and ABTS assays), antibacterial (disc diffusion assay on E. coli, S. aureus, B. subtilis, S. fecilis, and S. boydii), and anticancer (MTT assay on MCF-7, MDA-MB-231, U87, and DBTRG cell lines) potentialities which augmented the present investigation. The molecular docking analysis of title compounds against 3NM8 (DPPH) and 1DNU (ABTS) proteins for antioxidant activity; 5FGK (Gram-Positive Bacteria) and 1AB4 (Gram-Negative Bacteria) proteins for antibacterial activity; and 4GBD (MCF-7), 5FI2 (MDA-MB-231), 1D5R (U87), and 5TIJ (DBTRG) proteins for anticancer activity has affirmed the promising ligand-protein binding interactions among the hydroxy groups of the title compounds and aspartic acid of the concerned enzymatic proteins. The binding energy varying from -9.1645 to -7.7955 for Cosmosioside (1, Apigenin-7-glucoside) and from -9.2690 to -7.8306 for Cynaroside (2, Luteolin-7-glucoside) implies the isolated compounds as potential bioactive compounds. In addition, the performed studies like QSAR, ADMET, bioactivity properties, drug scores, and toxicity risks confirmed them as potential drug candidates and aspartic acid receptor antagonists. This research auxiliary augmented the existing array of phytological nanomedicines with new drug candidates that are credible with multiple bioactivities.
    Matched MeSH terms: Ligands
  3. Fulltext Plasmodium-infected erythrocytes induce secretion of IGFBP7 to form type II rosettes and escape phagocytosis
    Lee WC, Russell B, Sobota RM, Ghaffar K, Howland SW, Wong ZX, et al.
    Elife, 2020 Feb 18;9.
    PMID: 32066522 DOI: 10.7554/eLife.51546
    In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting hampers phagocytosis of IRBC by host phagocytes.
    Matched MeSH terms: Ligands
  4. Evolutionary trace analysis at the ligand binding site of laccase
    Mohamad SB, Ong AL, Ripen AM
    Bioinformation, 2008 Jun 18;2(9):369-72.
    PMID: 18795108
    Laccase belongs to the family of blue multi-copper oxidases and are capable of oxidizing a wide range of aromatic compounds. Laccases have industrial applications in paper pulping or bleaching and hydrocarbon bioremediation as a biocatalyst. We describe the design of a laccase with broader substrate spectrum in bioremediation. The application of evolutionary trace (ET) analysis of laccase at the ligand binding site for optimal design of the enzyme is described. In this attempt, class specific sites from ET analysis were mapped onto known crystal structure of laccase. The analysis revealed 162PHE as a critical residue in structure function relationship studies.
    Matched MeSH terms: Ligands
  5. The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer
    Lee WH, Loo CY, Leong CR, Young PM, Traini D, Rohanizadeh R
    Expert Opin Drug Deliv, 2017 08;14(8):937-957.
    PMID: 27759437 DOI: 10.1080/17425247.2017.1247804
    INTRODUCTION: The effectiveness of conventional cancer chemotherapy is hampered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle-based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer. Areas covered: This review focuses on the recent advances in the functionalization of nanocarriers with specific ligands, including antibodies, transferrin, folate, and peptides to overcome MDR cancer. The limitations of effective ligand-functionalized nanoparticles as well as therapeutic successes in ligand targeting are covered in the review. Expert opinion: Targeting MDR tumors with ligand-functionalized nanoparticles is a promising approach to improve the treatment of cancer. With this approach, higher drug concentrations at targeted sites would be achieved with lower dosage frequencies and reduced side effects in comparison to existing formulations of chemotherapeutic drugs. However, potential toxicities and immunological responses to ligands should be carefully reviewed for viable options in for future MDR cancer treatment.
    Matched MeSH terms: Ligands
  6. Fulltext Crystal structure of bis-(aceto-phenone 4-benzoyl-thio-semicarbazonato-κ(2) N (1),S)nickel(II)
    Kadir FK, Shamsuddin M, Rosli MM
    Acta Crystallogr E Crystallogr Commun, 2016 May 1;72(Pt 5):760-3.
    PMID: 27308036 DOI: 10.1107/S2056989016006873
    In the asymmetric unit of the title complex, [Ni(C16H14N3OS)2], the nickel ion is tetra-coordinated in a distorted square-planar geometry by two independent mol-ecules of the ligand which act as mononegative bidentate N,S-donors and form two five-membered chelate rings. The ligands are in trans (E) conformations with respect to the C=N bonds. The close approach of hydrogen atoms to the Ni(2+) atom suggests anagostic inter-actions (Ni⋯H-C) are present. The crystal structure is built up by a network of two C-H⋯O inter-actions. One of the inter-actions forms inversion dimers and the other links the mol-ecules into infinite chains parallel to [100]. In addition, a weak C-H⋯π inter-action is also present.
    Matched MeSH terms: Ligands
  7. Fulltext A Quantum-Based Similarity Method in Virtual Screening
    Al-Dabbagh MM, Salim N, Himmat M, Ahmed A, Saeed F
    Molecules, 2015;20(10):18107-27.
    PMID: 26445039 DOI: 10.3390/molecules201018107
    One of the most widely-used techniques for ligand-based virtual screening is similarity searching. This study adopted the concepts of quantum mechanics to present as state-of-the-art similarity method of molecules inspired from quantum theory. The representation of molecular compounds in mathematical quantum space plays a vital role in the development of quantum-based similarity approach. One of the key concepts of quantum theory is the use of complex numbers. Hence, this study proposed three various techniques to embed and to re-represent the molecular compounds to correspond with complex numbers format. The quantum-based similarity method that developed in this study depending on complex pure Hilbert space of molecules called Standard Quantum-Based (SQB). The recall of retrieved active molecules were at top 1% and top 5%, and significant test is used to evaluate our proposed methods. The MDL drug data report (MDDR), maximum unbiased validation (MUV) and Directory of Useful Decoys (DUD) data sets were used for experiments and were represented by 2D fingerprints. Simulated virtual screening experiment show that the effectiveness of SQB method was significantly increased due to the role of representational power of molecular compounds in complex numbers forms compared to Tanimoto benchmark similarity measure.
    Matched MeSH terms: Ligands
  8. Quantum probability ranking principle for ligand-based virtual screening
    Al-Dabbagh MM, Salim N, Himmat M, Ahmed A, Saeed F
    J Comput Aided Mol Des, 2017 Apr;31(4):365-378.
    PMID: 28220440 DOI: 10.1007/s10822-016-0003-4
    Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.
    Matched MeSH terms: Ligands
  9. Machine learning and molecular simulation ascertain antimicrobial peptide against Klebsiella pneumoniae from public database
    Al-Khdhairawi A, Sanuri D, Akbar R, Lam SD, Sugumar S, Ibrahim N, et al.
    Comput Biol Chem, 2023 Feb;102:107800.
    PMID: 36516617 DOI: 10.1016/j.compbiolchem.2022.107800
    Antimicrobial peptides (AMPs) are short peptides with a broad spectrum of antimicrobial activity. They play a key role in the host innate immunity of many organisms. The growing threat of microorganisms resistant to antimicrobial agents and the lack of new commercially available antibiotics have made in silico discovery of AMPs increasingly important. Machine learning (ML) has improved the speed and efficiency of AMP discovery while reducing the cost of experimental approaches. Despite various ML platforms developed, there is still a lack of integrative use of ML platforms for AMP discovery from publicly available protein databases. Therefore, our study aims to screen potential AMPs with antibiofilm properties from databases using ML platforms, followed by protein-peptide molecular docking analysis and molecular dynamics (MD) simulations. A total of 5850 peptides classified as non-AMP were screened from UniProtKB and analyzed using various online ML platforms (e.g., CAMPr3, DBAASP, dPABBs, Hemopred, and ToxinPred). Eight potential AMP peptides against Klebsiella pneumoniae with antibiofilm, non-toxic and non-hemolytic properties were then docked to MrkH, a transcriptional regulator of type 3 fimbriae involved in biofilm formation. Five of eight peptides bound more strongly than the native MrkH ligand when analyzed using HADDOCK and HPEPDOCK. Following the docking studies, our MD simulated that a Neuropeptide B (Peptide 3) bind strongly to the MrkH active sites. The discovery of putative AMPs that exceed the binding energies of the native ligand underscores the utility of the combined ML and molecular simulation strategies for discovering novel AMPs with antibiofilm properties.
    Matched MeSH terms: Ligands
  10. Fulltext Ligand-based virtual screening using Bayesian inference network and reweighted fragments
    Ahmed A, Abdo A, Salim N
    ScientificWorldJournal, 2012;2012:410914.
    PMID: 22623895 DOI: 10.1100/2012/410914
    Many of the similarity-based virtual screening approaches assume that molecular fragments that are not related to the biological activity carry the same weight as the important ones. This was the reason that led to the use of Bayesian networks as an alternative to existing tools for similarity-based virtual screening. In our recent work, the retrieval performance of the Bayesian inference network (BIN) was observed to improve significantly when molecular fragments were reweighted using the relevance feedback information. In this paper, a set of active reference structures were used to reweight the fragments in the reference structure. In this approach, higher weights were assigned to those fragments that occur more frequently in the set of active reference structures while others were penalized. Simulated virtual screening experiments with MDL Drug Data Report datasets showed that the proposed approach significantly improved the retrieval effectiveness of ligand-based virtual screening, especially when the active molecules being sought had a high degree of structural heterogeneity.
    Matched MeSH terms: Ligands*
  11. Ligand expansion in ligand-based virtual screening using relevance feedback
    Abdo A, Saeed F, Hamza H, Ahmed A, Salim N
    J Comput Aided Mol Des, 2012 Mar;26(3):279-87.
    PMID: 22249773 DOI: 10.1007/s10822-012-9543-4
    Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally-homogeneous sets of actives are being sought.
    Matched MeSH terms: Ligands
  12. New fragment weighting scheme for the Bayesian inference network in ligand-based virtual screening
    Abdo A, Salim N
    J Chem Inf Model, 2011 Jan 24;51(1):25-32.
    PMID: 21155550 DOI: 10.1021/ci100232h
    Many of the conventional similarity methods assume that molecular fragments that do not relate to biological activity carry the same weight as the important ones. One possible approach to this problem is to use the Bayesian inference network (BIN), which models molecules and reference structures as probabilistic inference networks. The relationships between molecules and reference structures in the Bayesian network are encoded using a set of conditional probability distributions, which can be estimated by the fragment weighting function, a function of the frequencies of the fragments in the molecule or the reference structure as well as throughout the collection. The weighting function combines one or more fragment weighting schemes. In this paper, we have investigated five different weighting functions and present a new fragment weighting scheme. Later on, these functions were modified to combine the new weighting scheme. Simulated virtual screening experiments with the MDL Drug Data Report (23) and maximum unbiased validation data sets show that the use of new weighting scheme can provide significantly more effective screening when compared with the use of current weighting schemes.
    Matched MeSH terms: Ligands
  13. Fulltext Hybrid-Enhanced Siamese Similarity Models in Ligand-Based Virtual Screen
    Altalib MK, Salim N
    Biomolecules, 2022 Nov 20;12(11).
    PMID: 36421733 DOI: 10.3390/biom12111719
    Information technology has become an integral aspect of the drug development process. The virtual screening process (VS) is a computational technique for screening chemical compounds in a reasonable amount of time and cost. The similarity search is one of the primary tasks in VS that estimates a molecule's similarity. It is predicated on the idea that molecules with similar structures may also have similar activities. Many techniques for comparing the biological similarity between a target compound and each compound in the database have been established. Although the approaches have a strong performance, particularly when dealing with molecules with homogenous active structural, they are not enough good when dealing with structurally heterogeneous compounds. The previous works examined many deep learning methods in the enhanced Siamese similarity model and demonstrated that the Enhanced Siamese Multi-Layer Perceptron similarity model (SMLP) and the Siamese Convolutional Neural Network-one dimension similarity model (SCNN1D) have good outcomes when dealing with structurally heterogeneous molecules. To further improve the retrieval effectiveness of the similarity model, we incorporate the best two models in one hybrid model. The reason is that each method gives good results in some classes, so combining them in one hybrid model may improve the retrieval recall. Many designs of the hybrid models will be tested in this study. Several experiments on real-world data sets were conducted, and the findings demonstrated that the new approaches outperformed the previous method.
    Matched MeSH terms: Ligands
  14. Testosterone decreases the expression of endometrial pinopode and L-selectin ligand (MECA-79) in adult female rats during uterine receptivity period
    Mokhtar HM, Giribabu N, Muniandy S, Salleh N
    Int J Clin Exp Pathol, 2014;7(5):1967-76.
    PMID: 24966906
    Pinopode, a progesterone-dependent endometrial projection which appears during uterine receptivity period, participates in blastocyst implantation. Blastocyst loosely attaches to pinopode via L-selectin ligand (MECA-79). We hypothesized that pinopode and MECA-79 expressions were affected by testosterone. Therefore, the effect of testosterone on pinopode and MECA-79 expressions during uterine receptivity period were investigated.
    Matched MeSH terms: Ligands
  15. Fulltext Docking Studies and Molecular Dynamics Simulation of Ipomoea batatas L. Leaves Compounds as Lipoxygenase (LOX) Inhibitor
    Yeni Y, Supandi S, Dwita LP, Suswandari S, Shaharun MS, Sambudi NS
    J Pharm Bioallied Sci, 2020 Nov;12(Suppl 2):S836-S840.
    PMID: 33828386 DOI: 10.4103/jpbs.JPBS_103_20
    Background: Inflammatory mediators produced by cyclooxygenase (COX) and lipoxygenase (LOX) pathways are responsible for many human diseases, such as cancer, arthritis, and neurological disorders. Flavonoid-containing plants, such as Ipomoea batatas leaves, have shown potential anti-inflammatory activity.

    Objectives: This study aimed to predict the actions of 10 compounds in I. batatas leaves, which are YGM-0a [cyanidin 3-0-sophoroside-5-0-glucosede], YGM-0f [cyanidin 3-O-(2-0-(6-0-(E)-p-coumaroyl-β-D-glucopyranosyl)-β-D-glucopyranoside)-5-0-β-D-glucopyranoside], YGM-1a [cyanidin 3-(6,6'-caffeylp-hydroxybenzoylsophoroside) -5-glucoside], YGM-1b [cyanidin 3-(6,6'-dicaffeylsophor-oside)-5-glucoside], YGM-2 [cyanidin 3-(6-caffeylsophoroside)-5-glucoside], YGM-3 [cyanidin 3-(6,6'-caffeyl-ferulylsophoroside)-5-glucoside], YGM-4b [peonidin 3-(6,6'-dicaffeylsophoroside)-5- glucoside], YGM-5a [peonidin 3-(6,6'-caffeylphydroxybenzo-ylsophoroside)-5-gluco-side], YGM-5b [cyanidin 3-6-caffeylsophoroside)-5-glucosede], and YGM-6 [peonidin 3-(6,6'-caffeylferulylsophoroside)-5-glucoside] as LOX inhibitors, and also predict the stability of ligand-LOX complex.

    Materials and Methods: The compounds were screened through docking studies using PLANTS. Also, the molecular dynamics simulation was conducted using GROMACS at 310K.

    Results: The results showed that the most significant binding affinity toward LOX was shown by YGM-0a and YGM-0a, and the LOX complex in molecular dynamics simulation showed stability for 20 ns.

    Conclusion: Based on Docking Studies and Molecular Dynamics Simulation of I. Batatas Leaves compounds, YGM-0a was shown to be the most probable LOX inhibitor.

    Matched MeSH terms: Ligands
  16. Converting differential-equation models of biological systems to membrane computing
    Muniyandi RC, Zin AM, Sanders JW
    Biosystems, 2013 Dec;114(3):219-26.
    PMID: 24120990 DOI: 10.1016/j.biosystems.2013.09.008
    This paper presents a method to convert the deterministic, continuous representation of a biological system by ordinary differential equations into a non-deterministic, discrete membrane computation. The dynamics of the membrane computation is governed by rewrite rules operating at certain rates. That has the advantage of applying accurately to small systems, and to expressing rates of change that are determined locally, by region, but not necessary globally. Such spatial information augments the standard differentiable approach to provide a more realistic model. A biological case study of the ligand-receptor network of protein TGF-β is used to validate the effectiveness of the conversion method. It demonstrates the sense in which the behaviours and properties of the system are better preserved in the membrane computing model, suggesting that the proposed conversion method may prove useful for biological systems in particular.
    Matched MeSH terms: Ligands
  17. Ion-Imprinted Polymer for Selective Separation of Cerium(III) Ions from Rare Earth Mixture
    Rahman ML, Puah PY, Sarjadi MS, Arshad SE, Musta B, Sarkar SM
    J Nanosci Nanotechnol, 2019 09 01;19(9):5796-5802.
    PMID: 30961741 DOI: 10.1166/jnn.2019.16538
    Ion-imprinting polymers (IIPs) materials draw the great recognition because of the powerful selectivity to the desired metal ions. Therefore, the ion-imprinting polymer (Ce-IIP) was prepared by using cerium metal with amidoxime ligand as the complexing agent, in addition ethylene glycol dimethacrylate (EGDMA) and 2,2-azobisisobutyronitrile (AIBN) are crosslinking agent and free radical initiator, respectively. Aqueous HCl was applied to leach the cerium ions from the imprinted polymer for the creation of cavities of template, which is utilized for further cerium ions adsorption with high selectivity. The Ce-IIP was characterized by using ICP-MS, FE-SEM and also solid state analysis by UV-vis NIR spectroscopy. FT-IR study confirmed the complexation of the Ce-IIP was successful. The optimum pH was found to be 6 and the highest adsorption capacity was estimated about 145 mg g-1. Thus, the prepared Ce-IIP gave very good selectivity to cerium ions in the presence of lanthanide ions and also Ce-IIP can be reused 10 times without a substantial loss in adsorption capacity.
    Matched MeSH terms: Ligands
  18. Fulltext Common variants of chemokine receptor gene CXCR3 and its ligands CXCL10 and CXCL11 associated with vascular permeability of dengue infection in peninsular Malaysia
    Hoh BP, Umi-Shakina H, Zuraihan Z, Zaiharina MZ, Rafidah-Hanim S, Mahiran M, et al.
    Hum Immunol, 2015 Jun;76(6):421-6.
    PMID: 25858769 DOI: 10.1016/j.humimm.2015.03.019
    Dengue causes significantly more human disease than any other arboviruses. It causes a spectrum of illness, ranging from mild self-limited fever, to severe and fatal dengue hemorrhagic fever, as evidenced by vascular leakage and multifactorial hemostatic abnormalities. There is no specific treatment available till date. Evidence shows that chemokines CXCL10, CXCL11 and their receptor CXCR3 are involved in severity of dengue, but their genetic association with the susceptibility of vascular leakage during dengue infection has not been reported. We genotyped 14 common variants of these candidate genes in 176 patients infected with dengue. rs4859584 and rs8878 (CXCL10) were significantly associated with vascular permeability of dengue infection (P<0.05); while variants of CXCL11 showed moderate significance of association (P=0.0527). Haplotype blocks were constructed for genes CXCL10 and CXCL11 (5 and 7 common variants respectively). Haplotype association tests performed revealed that, "CCCCA" of gene CXCL10 and "AGTTTAC" of CXCL11 were found to be significantly associated with vascular leakage (P=0.0154 and 0.0366 respectively). In summary, our association study further strengthens the evidence of the involvement of CXCL10 and CXCL11 in the pathogenesis of dengue infection.
    Matched MeSH terms: Ligands
  19. Elucidating isoniazid resistance using molecular modeling
    Wahab HA, Choong YS, Ibrahim P, Sadikun A, Scior T
    J Chem Inf Model, 2009 Jan;49(1):97-107.
    PMID: 19067649 DOI: 10.1021/ci8001342
    The continuing rise in tuberculosis incidence and the problem of drug resistance strains have prompted the research on new drug candidates and the mechanism of drug resistance. Molecular docking and molecular dynamics simulation (MD) were performed to study the binding of isoniazid onto the active site of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) in an attempt to address the mycobacterial resistance against isoniazid. Results show that isonicotinic acyl-NADH (INADH) has an extremely high binding affinity toward the wild type InhA by forming stronger interactions compared to the parent drug (isoniazid) (INH). Due to the increase of hydrophobicity and reduction in the side chain's volume of A94 of mutant type InhA, both INADH and the mutated protein become more mobile. Due to this reason, the molecular interactions of INADH with mutant type are weaker than that observed with the wild type. However, the reduced interaction caused by the fluctuation of INADH and the mutant protein only inflected minor resistance in the mutant strain as inferred from free energy calculation. MD results also showed there exists a water-mediated hydrogen bond between INADH and InhA. However, the bridged water molecule is only present in the INADH-wild type complex, reflecting the putative role of the water molecule in the binding of INADH to the wild type protein. The results support the assumption that the conversion of prodrug isoniazid into its active form INADH is mediated by KatG as a necessary step prior to target binding on InhA. Our findings also contribute to a better understanding of INH resistance in mutant type.
    Matched MeSH terms: Ligands
  20. Fulltext Thermodynamics of semi-specific ligand recognition: the binding of dipeptides to the E.coli dipeptide binding protein DppA
    Zainol MKM, Linforth RJC, Winzor DJ, Scott DJ
    Eur Biophys J, 2021 Dec;50(8):1103-1110.
    PMID: 34611772 DOI: 10.1007/s00249-021-01572-y
    This investigation of the temperature dependence of DppA interactions with a subset of three dipeptides (AA. AF and FA) by isothermal titration calorimetry has revealed the negative heat capacity ([Formula: see text]) that is a characteristic of hydrophobic interactions. The observation of enthalpy-entropy compensation is interpreted in terms of the increased structuring of water molecules trapped in a hydrophobic environment, the enthalpic energy gain from which is automatically countered by the entropy decrease associated with consequent loss of water structure flexibility. Specificity for dipeptides stems from appropriate spacing of designated DppA aspartate and arginine residues for electrostatic interaction with the terminal amino and carboxyl groups of a dipeptide, after which the binding pocket closes to become completely isolated from the aqueous environment. Any differences in chemical reactivity of the dipeptide sidechains are thereby modulated by their occurrence in a hydrophobic environment where changes in the structural state of entrapped water molecules give rise to the phenomenon of enthalpy-entropy compensation. The consequent minimization of differences in the value of ΔG0 for all DppA-dipeptide interactions thus provides thermodynamic insight into the biological role of DppA as a transporter of all dipeptides across the periplasmic membrane.
    Matched MeSH terms: Ligands
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