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Computer-Aided Antibody Design: An Overview

Choong YS, Lee YV, Soong JX, Law CT, Lim YY

Adv Exp Med Biol, 2017;1053:221-243.
PMID: 29549642 DOI: 10.1007/978-3-319-72077-7_11

The use of monoclonal antibody as the next generation protein therapeutics with remarkable success has surged the development of antibody engineering to design molecules for optimizing affinity, better efficacy, greater safety and therapeutic function. Therefore, computational methods have become increasingly important to generate hypotheses, interpret and guide experimental works. In this chapter, we discussed the overall antibody design by computational approches.

Matched MeSH terms: Binding Sites, Antibody
Fulltext Structural Basis of Specific Glucoimidazole and Mannoimidazole Binding by Os3BGlu7

Nutho B, Pengthaisong S, Tankrathok A, Lee VS, Ketudat Cairns JR, Rungrotmongkol T, et al.

Biomolecules, 2020 Jun 15;10(6).
PMID: 32549280 DOI: 10.3390/biom10060907

β-Glucosidases and β-mannosidases hydrolyze substrates that differ only in the epimer of the nonreducing terminal sugar moiety, but most such enzymes show a strong preference for one activity or the other. Rice Os3BGlu7 and Os7BGlu26 β-glycosidases show a less strong preference, but Os3BGlu7 and Os7BGlu26 prefer glucosides and mannosides, respectively. Previous studies of crystal structures with glucoimidazole (GIm) and mannoimidazole (MIm) complexes and metadynamic simulations suggested that Os7BGlu26 hydrolyzes mannosides via the B2,5 transition state (TS) conformation preferred for mannosides and glucosides via their preferred 4H3/4E TS conformation. However, MIm is weakly bound by both enzymes. In the present study, we found that MIm was not bound in the active site of crystallized Os3BGlu7, but GIm was tightly bound in the -1 subsite in a 4H3/4E conformation via hydrogen bonds with the surrounding residues. One-microsecond molecular dynamics simulations showed that GIm was stably bound in the Os3BGlu7 active site and the glycone-binding site with little distortion. In contrast, MIm initialized in the B2,5 conformation rapidly relaxed to a E3/4H3 conformation and moved out into a position in the entrance of the active site, where it bound more stably despite making fewer interactions. The lack of MIm binding in the glycone site in protein crystals and simulations implies that the energy required to distort MIm to the B2,5 conformation for optimal active site residue interactions is sufficient to offset the energy of those interactions in Os3BGlu7. This balance between distortion and binding energy may also provide a rationale for glucosidase versus mannosidase specificity in plant β-glycosidases.

Matched MeSH terms: Binding Sites
Fulltext Cross-Neutralizing CRF01_AE-Infected Plasma from Malaysia Targets CD4-Binding Site of Human Immunodeficiency Virus Type-1 Envelope Glycoprotein

Ng QR, Tee KK, Binley JM, Tong T

AIDS Res Hum Retroviruses, 2022 Feb;38(2):162-172.
PMID: 34006141 DOI: 10.1089/AID.2020.0299

Human immunodeficiency virus type-1 (HIV-1) antigenic variation poses a great challenge for vaccine immunogen design to elicit broadly neutralizing antibodies (bNAbs). Over the last 10-15 years, great progress has been made to understand the conserved sites of sensitivity on HIV envelope glycoprotein spikes targeted by bNAbs. Plasma neutralization mapping and monoclonal antibody isolation efforts have revealed five major conserved epitope clusters. Most of this work has focused on subtype B and C-infected Caucasian or African donors. It is not clear if the same epitopes and epitope rank order preferences are also true in donors infected with different HIV-1 subtypes and with different racial backgrounds. To investigate this point, in this study we report the first attempt to profile the bNAb specificities of CRF01_AE-infected Malaysian plasmas. We first measured neutralization titers of 21 plasmas against a subtype A, B, and AE pseudovirus panel. This revealed that 14% (3 of 21) plasmas had cross-clade breadth. Focusing on the cross-neutralizing plasma P9, we used AE and JR-FL mutant pseudoviruses, gp120 monomer interference, and native polyacrylamide gel electrophoresis to better understand the neutralization specificity. P9 demonstrates CD4-binding-site specificity with trimer dependence and D368 independence.

Matched MeSH terms: Binding Sites
Computational docking of L-arginine and its structural analogues to C-terminal domain of Escherichia coli arginine repressor protein (ArgRc)

Kueh R, Rahman NA, Merican AF

J Mol Model, 2003 Apr;9(2):88-98.
PMID: 12707802

The arginine repressor (ArgR) of Escherichia coli binds to six L-arginine molecules that act as its co-repressor in order to bind to DNA. The binding of L-arginine molecules as well as its structural analogues is compared by means of computational docking. A grid-based energy evaluation method combined with a Monte Carlo simulated annealing process was used in the automated docking. For all ligands, the docking procedure proposed more than one binding site in the C-terminal domain of ArgR (ArgRc). Interaction patterns of ArgRc with L-arginine were also observed for L-canavanine and L-citrulline. L-lysine and L-homoarginine, on the other hand, were shown to bind poorly at the binding site. Figure A general overview of the sites found from docking the various ligands into ArgRc ( grey ribbons). Red coloured sticks: residues in binding site H that was selected for docking

Matched MeSH terms: Binding Sites
Fulltext Molecular interaction of fibrinogen with zeolite nanoparticles

Derakhshankhah H, Hosseini A, Taghavi F, Jafari S, Lotfabadi A, Ejtehadi MR, et al.

Sci Rep, 2019 02 07;9(1):1558.
PMID: 30733474 DOI: 10.1038/s41598-018-37621-4

Fibrinogen is one of the key proteins that participate in the protein corona composition of many types of nanoparticles (NPs), and its conformational changes are crucial for activation of immune systems. Recently, we demonstrated that the fibrinogen highly contributed in the protein corona composition at the surface of zeolite nanoparticles. Therefore, understanding the interaction of fibrinogen with zeolite nanoparticles in more details could shed light of their safe applications in medicine. Thus, we probed the molecular interactions between fibrinogen and zeolite nanoparticles using both experimental and simulation approaches. The results indicated that fibrinogen has a strong and thermodynamically favorable interaction with zeolite nanoparticles in a non-cooperative manner. Additionally, fibrinogen experienced a substantial conformational change in the presence of zeolite nanoparticles through a concentration-dependent manner. Simulation results showed that both E- and D-domain of fibrinogen are bound to the EMT zeolite NPs via strong electrostatic interactions, and undergo structural changes leading to exposing normally buried sequences. D-domain has more contribution in this interaction and the C-terminus of γ chain (γ377-394), located in D-domain, showed the highest level of exposure compared to other sequences/residues.

Matched MeSH terms: Binding Sites
Fulltext The conformational dynamics of H2-H3n and S2-H6 in gating ligand entry into the buried binding cavity of vitamin D receptor

Tee WV, Ripen AM, Mohamad SB

Sci Rep, 2016 Oct 27;6:35937.
PMID: 27786277 DOI: 10.1038/srep35937

Crystal structures of holo vitamin D receptor (VDR) revealed a canonical conformation in which the ligand is entrapped in a hydrophobic cavity buried in the ligand-binding domain (LBD). The mousetrap model postulates that helix 12 is positioned away from the domain to expose the interior cavity. However, the extended form of helix 12 is likely due to artifacts during crystallization. In this study, we set out to investigate conformational dynamics of apo VDR using molecular dynamics simulation on microsecond timescale. Here we show the neighboring backbones of helix 2-helix 3n and beta strand 2-helix 6 of LBD, instead of the helix 12, undergo large-scale motion, possibly gating the entrance of ligand to the ligand binding domain. Docking analysis to the simulated open structure of VDR with the estimated free energy of -37.0 kJ/mol, would emphasise the role of H2-H3n and S2-H6 in facilitating the entrance of calcitriol to the LBD of VDR.

Matched MeSH terms: Binding Sites
Fulltext Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and Their Interactions with ACE2

Hatmal MM, Alshaer W, Al-Hatamleh MAI, Hatmal M, Smadi O, Taha MO, et al.

Cells, 2020 Dec 08;9(12).
PMID: 33302501 DOI: 10.3390/cells9122638

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) are highly similar genetically and at the protein production level, there are significant differences between them. Research has shown that the structural spike (S) protein plays an important role in the evolution and transmission of SARS-CoV-2. So far, studies have shown that various genes encoding primarily for elements of S protein undergo frequent mutation. We have performed an in-depth review of the literature covering the structural and mutational aspects of S protein in the context of SARS-CoV-2, and compared them with those of SARS-CoV and MERS-CoV. Our analytical approach consisted in an initial genome and transcriptome analysis, followed by primary, secondary and tertiary protein structure analysis. Additionally, we investigated the potential effects of these differences on the S protein binding and interactions to angiotensin-converting enzyme 2 (ACE2), and we established, after extensive analysis of previous research articles, that SARS-CoV-2 and SARS-CoV use different ends/regions in S protein receptor-binding motif (RBM) and different types of interactions for their chief binding with ACE2. These differences may have significant implications on pathogenesis, entry and ability to infect intermediate hosts for these coronaviruses. This review comprehensively addresses in detail the variations in S protein, its receptor-binding characteristics and detailed structural interactions, the process of cleavage involved in priming, as well as other differences between coronaviruses.

Matched MeSH terms: Binding Sites
A head-to-head comparison of MM/PBSA and MM/GBSA in predicting binding affinities for the CB1 cannabinoid ligands

Yau MQ, Liew CWY, Toh JH, Loo JSE

J Mol Model, 2024 Oct 31;30(11):390.
PMID: 39480515 DOI: 10.1007/s00894-024-06189-4

CONTEXT: The substantial increase in the number of active and inactive-state CB1 receptor experimental structures has provided opportunities for CB1 drug discovery using various structure-based drug design methods, including the popular end-point methods for predicting binding free energies-Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA). In this study, we have therefore evaluated the performance of MM/PBSA and MM/GBSA in calculating binding free energies for CB1 receptor. Additionally, with both MM/PBSA and MM/GBSA being known for their highly individualized performance, we have evaluated the effects of various simulation parameters including the use of energy minimized structures, choice of solute dielectric constant, inclusion of entropy, and the effects of the five GB models. Generally, MM/GBSA provided higher correlations than MM/PBSA (rMM/GBSA = 0.433 - 0.652 vs. rMM/PBSA = 0.100 - 0.486) regardless of the simulation parameters, while also offering faster calculations. Improved correlations were observed with the use of molecular dynamics ensembles compared with energy minimized structures and larger solute dielectric constants. Incorporation of entropic terms led to unfavorable results for both MM/PBSA and MM/GBSA for a majority of the dataset, while the evaluation of the various GB models exerted a varying effect on both the datasets. The findings obtained in this study demonstrate the utility of MM/PBSA and MM/GBSA in predicting binding free energies for the CB1 receptor, hence providing a useful benchmark for their applicability in the endocannabinoid system as well as other G protein-coupled receptors.
METHODS: The study utilized the docked dataset (Induced Fit Docking with Glide XP scoring function) from Loo et al., consisting of 46 ligands-23 agonists and 23 antagonists. The equilibrated structures from Loo et al. were subjected to 30 ns production simulations using GROMACS 2018 at 300 K and 1 atm with the velocity rescaling thermostat and the Parinello-Rahman barostat. AMBER ff99SB*-ILDN was used for the proteins, General Amber Force Field (GAFF) was used for the ligands, and Slipids parameters were used for lipids. MM/PBSA and MM/GBSA binding free energies were then calculated using gmx_MMPBSA. The solute dielectric constant was varied between 1, 2, and 4 to study the effect of different solute dielectric constants on the performance of MM/PB(GB)SA. The effect of entropy on MM/PB(GB)SA binding free energies was evaluated using the interaction entropy module implemented in gmx_MMPBSA. Five GB models, GBHCT, GBOBC1, GBOBC2, GBNeck, and GBNeck2, were evaluated to study the effect of the choice of GB models in the performance of MM/GBSA. Pearson correlation coefficients were used to measure the correlation between experimental and predicted binding free energies.

Matched MeSH terms: Binding Sites
Identification of the cell binding domain in Nipah virus G glycoprotein using a phage display system

Lam CW, AbuBakar S, Chang LY

J Virol Methods, 2017 05;243:1-9.
PMID: 28082163 DOI: 10.1016/j.jviromet.2017.01.004

Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus with unusual broad host tropism and is designated as a Category C pathogen by the U.S. National Institute of Allergy and Infectious Diseases. NiV infection is initiated after binding of the viral G glycoprotein to the host cell receptor. The aim of this study was to map the NiV G glycoprotein cell binding domain using a phage display system. The NiV G extracellular domain was truncated and displayed as attachment proteins on M13 phage g3p minor coat protein. The binding efficiency of recombinant phages displaying different regions of NiV G to mammalian cells was evaluated. Results showed that regions of NiV G consisting of amino acids 396-602 (recombinant phage G4) and 498-602 (recombinant phage G5) demonstrated the highest binding to both Vero (5.5×103 cfu/ml and 5.6×103 cfu/ml) and THP-1 cells (3.5×103 cfu/ml and 2.9×103 cfu/ml). However, the binding of both of these recombinant phages to THP-1 cells was significantly lower than to Vero cells, and this could be due to the lack of primary host cell receptor expression on THP-1 cells. Furthermore, the binding between these two recombinant phages was competitive suggesting that there was a common host cell attachment site. This study employed an approach that is suitable for use in a biosafety level 2 containment laboratory without the need to use live virus to show that NiV G amino acids 498-602 play an important role for attachment to host cells.

Matched MeSH terms: Binding Sites
Supramolecular interaction of 6-shogaol, a therapeutic agent of Zingiber officinale with human serum albumin as elucidated by spectroscopic, calorimetric and molecular docking methods

Feroz SR, Mohamad SB, Lee GS, Malek SN, Tayyab S

Phytomedicine, 2015 Jun 01;22(6):621-30.
PMID: 26055127 DOI: 10.1016/j.phymed.2015.03.016

BACKGROUND: 6-Shogaol, one of the main bioactive constituents of Zingiber officinale has been shown to possess various therapeutic properties. Interaction of a therapeutic compound with plasma proteins greatly affects its pharmacokinetic and pharmacodynamic properties.
PURPOSE: The present investigation was undertaken to characterize the interaction between 6-shogaol and the main in vivo transporter, human serum albumin (HSA).
METHODS: Various binding characteristics of 6-shogaol-HSA interaction were studied using fluorescence spectroscopy. Thermal stability of 6-shogaol-HSA system was determined by circular dichroism (CD) and differential scanning calorimetric (DSC) techniques. Identification of the 6-shogaol binding site on HSA was made by competitive drug displacement and molecular docking experiments.
RESULTS: Fluorescence quench titration results revealed the association constant, Ka of 6-shogaol-HSA interaction as 6.29 ± 0.33 × 10(4) M(-1) at 25 ºC. Values of the enthalpy change (-11.76 kJ mol(-1)) and the entropy change (52.52 J mol(-1) K(-1)), obtained for the binding reaction suggested involvement of hydrophobic and van der Waals forces along with hydrogen bonds in the complex formation. Higher thermal stability of HSA was noticed in the presence of 6-shogaol, as revealed by DSC and thermal denaturation profiles. Competitive ligand displacement experiments along with molecular docking results suggested the binding preference of 6-shogaol for Sudlow's site I of HSA.
CONCLUSION: All these results suggest that 6-shogaol binds to Sudlow's site I of HSA through moderate binding affinity and involves hydrophobic and van der Waals forces along with hydrogen bonds.

Matched MeSH terms: Binding Sites
Bromophenol blue binding to mammalian albumins and displacement of albumin-bound bilirubin

Kim BB, Abdul Kadir H, Tayyab S

Pak J Biol Sci, 2008 Oct 15;11(20):2418-22.
PMID: 19137852

Interaction of bromophenol blue (BPB) with serum albumins from different mammalian species, namely, human (HSA), bovine (BSA), goat (GSA), sheep (SSA), rabbit (RbSA), porcine (PSA) and dog (DSA) was studied using absorption and absorption difference spectroscopy. BPB-albumin complexes showed significant differences in the spectral characteristics, i.e., extent of bathochromic shift and hypochromism relative to the spectral features of free BPB. Absorption difference spectra of these complexes also showed variations in the position of maxima and absorption difference (deltaAbs.) values. Absorption difference spectra of different bilirubin (BR)-albumin complexes showed a significant blue shift accompanied by decrease in deltaAbs. values in presence of BPB which were indicative of the displacement of bound BR from its binding site in BR-albumin complexes. These changes in the difference spectral characteristics of BR-albumin complexes were more marked at higher BPB concentration. However, the extent of these changes was different for different BR-albumin complexes. Taken together, all these results suggest that BPB partially shares BR binding site on albumin and different mammalian albumins show differences in the microenvironment of the BR/BPB binding site.

Matched MeSH terms: Binding Sites
Exploring the potential of biologically active phenolic acids from marine natural products as anticancer agents targeting the epidermal growth factor receptor

Roney M, Issahaku AR, Huq AM, Soliman MES, Tajuddin SN, Aluwi MFFM

J Biomol Struct Dyn, 2024;42(24):13564-13587.
PMID: 37909584 DOI: 10.1080/07391102.2023.2276879

The epidermal growth factor receptor (EGFR) dimerizes upon ligand bindings to the extracellular domain that initiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphorylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. The main objective of this research is to discover more promising anti-cancer lead compound against EGRF from the phenolic acids of marine natural products using in-silico approaches. Phenolic compounds reported from marine sources are reviewed from previous literatures. Furthermore, molecular docking was carried out using the online tool CB-Dock. The molecules with good docking and binding energies scores were subjected to ADME, toxicity and drug-likeness analysis. Subsequently, molecules from the docking experiments were also evaluated using the acute toxicity and MD simulation studies. Fourteen phenolic compounds from the reported literatures were reviewed based on the findings, isolation, characterized and applications. Molecular docking studies proved that the phenolic acids have good binding fitting by forming hydrogen bonds with amino acid residues at the binding site of EGFR. Chlorogenic acid, Chicoric acid and Rosmarinic acid showed the best binding energies score and forming hydrogen bonds with amino acid residues compare to the reference drug Erlotinib. Among these compounds, Rosmarinic acid showed the good pharmacokinetics profiles as well as acute toxicity profile. The MD simulation study further revealed that the lead complex is stable and could be future drug to treat the cancer disease. Furthermore, in a wet lab environment, both in-vitro and in-vivo testing will be employed to validate the existing computational results.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Binding Sites
In silico development of potential InhA inhibitors through 3D-QSAR analysis, virtual screening and molecular dynamics

Bhaskar V, Kumar S, Sujathan Nair A, Gokul S, Rajappan Krishnendu P, Benny S, et al.

J Biomol Struct Dyn, 2025 Feb;43(3):1329-1351.
PMID: 38064315 DOI: 10.1080/07391102.2023.2291549

Tuberculosis is one of the most ancient infectious diseases known to mankind predating upper Paleolithic era. In the current scenario, treatment of drug resistance tuberculosis is the major challenge as the treatment options are limited, less efficient and more toxic. In our study we have developed an atom based 3D QSAR model, statistically validated sound with R2 > 0.90 and Q2 > 0.72 using reported direct inhibitors of InhA (2018-2022), validated by enzyme inhibition assay. The model was used to screen a library of 3958 molecules taken from Binding DB and candidates molecules with promising predicted activity value (pIC50) > 5) were selected for further analyzed screening by using molecular docking, ADME profiling and molecular dynamic simulations. The lead molecule, ZINC11536150 exhibited good docking score (glideXP = -11.634 kcal/mol) compared to standard triclosan (glideXP = -7.129 kcal/mol kcal/mol) and through molecular dynamics study it was observed that the 2nv6-complex of ZINC11536150 with Mycobacterium tuberculosis InhA (PDB entry: 2NV6) complex remained stable throughout the entire simulation time of 100 ns.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Binding Sites
High-throughput virtual screening, pharmacophore modelling and antagonist effects of small molecule inhibitors against cytotoxin-induced cytotoxicity

Lim EQ, Ahemad N, Yap MKK

J Biomol Struct Dyn, 2025 Mar;43(4):2014-2028.
PMID: 38100546 DOI: 10.1080/07391102.2023.2293275

Cobra venom cytotoxins (CTX) cause dermonecrosis in envenomed patients who suffered from limb amputations due to the limitation of serotherapy-based antivenoms. This study aimed to identify small molecule inhibitors against CTX. A structure-based high-throughput virtual screening (HTVS) was conducted based on a conserved CTX, using the Natural Product Activity and Species Source (NPASS) screening library. The hits were valerenic acid, 1-oxo-2H-isoquinoline-4-carboxylic acid, acenaphthene, and 5-bromopyrrole-2-carboxamide, which interacted with contemporary antivenom binding site A and functional loops I-III of CTX, respectively, in molecular docking studies. Furthermore, molecular dynamic simulations were performed along with analysis of ligand fitness through their pharmacophore and pharmacokinetics properties. The antagonist effects of these hits on CTX-induced cytotoxicity were examined in human keratinocytes (HaCaT). Despite having a low binding affinity (KD = 14.45 × 10-4 M), acenaphthene demonstrated a significant increase of cell viability at 6 h and 24 h in experimental envenomed HaCaT. It also demonstrated the highest neutralization potency against CTX with a median effective concentration (EC50) of 0.05 mL/mg. Acenaphthene interacted with the functional loop II, which is the crucial cytotoxic site of CTX. It has an aromatic ring as its primary pharmacophoric feature, commonly used for rational drug design. In conclusion, acenaphthene could be a promising lead compound as a small molecule inhibitor.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Binding Sites
Regulation of gene expression mediating indeterminate muscle growth in teleosts

Ahammad AK, Asaduzzaman M, Asakawa S, Watabe S, Kinoshita S

Mech. Dev., 2015 Aug;137:53-65.
PMID: 25842264 DOI: 10.1016/j.mod.2015.02.006

Teleosts are unique among vertebrates due to their indeterminate muscle growth, i.e., continued production of neonatal muscle fibers until death. However, the molecular mechanism(s) underlying this property is unknown. Here, we focused on the torafugu (Takifugu rubripes) myosin heavy chain gene, MYHM2528-1, which is specifically expressed in neonatal muscle fibers produced by indeterminate muscle growth. We examined the flanking region of MYHM2528-1 through an in vivo reporter assay using zebrafish (Danio rerio) and identified a 2100 bp 5'-flanking sequence that contained sufficient promoter activity to allow specific gene expression. The effects of enhanced promoter activity were observed at the outer region of the fast muscle and the dorsal edge of slow muscle in zebrafish larvae. At the juvenile stage, the promoter was specifically activated in small diameter muscle fibers scattered throughout fast muscle and in slow muscle near the septum separating slow and fast muscles. This spatio-temporal promoter activity overlapped with known myogenic zones involved in teleost indeterminate muscle growth. A deletion mutant analysis revealed that the -2100 to -600 bp 5'flanking sequence of MYHM2528-1 is essential for promoter activity. This region contains putative binding sites for several representative myogenesis-related transcription factors and nuclear factor of activated T-cell (NFAT), a transcription activator involved in regeneration of mammalian adult skeletal muscle. A significant reduction in the promoter activity of the MYHM2528-1 deletion constructs was observed in accordance with a reduction in the number of these binding sites, suggesting the involvement of specific transcription factors in indeterminate muscle growth.

Matched MeSH terms: Binding Sites/genetics
Interleukin-6 inhibition of peroxisome proliferator-activated receptor alpha expression is mediated by JAK2- and PI3K-induced STAT1/3 in HepG2 hepatocyte cells

Chew GS, Myers S, Shu-Chien AC, Muhammad TS

Mol Cell Biochem, 2014 Mar;388(1-2):25-37.
PMID: 24242046 DOI: 10.1007/s11010-013-1896-z

Interleukin-6 (IL-6) is the major activator of the acute phase response (APR). One important regulator of IL-6-activated APR is peroxisome proliferator-activated receptor alpha (PPARα). Currently, there is a growing interest in determining the role of PPARα in regulating APR; however, studies on the molecular mechanisms and signaling pathways implicated in mediating the effects of IL-6 on the expression of PPARα are limited. We previously revealed that IL-6 inhibits PPARα gene expression through CAAT/enhancer-binding protein transcription factors in hepatocytes. In this study, we determined that STAT1/3 was the direct downstream molecules that mediated the Janus kinase 2 (JAK2) and phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways in IL-6-induced repression of PPARα. Treatment of cells with pharmacological inhibitors of JAK2, PI3K, AKT, and mTOR attenuated the inhibitory effect of IL-6 on PPARα protein in a dose-dependent manner. These inhibitors also decreased the IL-6-induced repression of PPARα mRNA expression and promoter activity. Overexpression of STAT1 and STAT3 in HepG2 cells cotransfected with a reporter vector containing this PPARα promoter region revealed that both the expression plasmids inhibited the IL-6-induced repression of PPARα promoter activity. In the presence of inhibitors of JAK2 and mTOR (AG490 and rapamycin, respectively), IL-6-regulated protein expression and DNA binding of STAT1 and STAT3 were either completely or partially inhibited simultaneously, and the IL-6-induced repression of PPARα protein and mRNA was also inhibited. This study has unraveled novel pathways by which IL-6 inhibits PPARα gene transcription, involving the modulation of JAK2/STAT1-3 and PI3K/AKT/mTOR by inducing the binding of STAT1 and STAT3 to STAT-binding sites on the PPARα promoter. Together, these findings represent a new model of IL-6-induced suppression of PPARα expression by inducing STAT1 and STAT3 phosphorylation and subsequent down-regulation of PPARα mRNA expression.

Matched MeSH terms: Binding Sites/genetics
Molecular docking study on platelet-activating factor antagonistic activity of bioactive compounds isolated from Guttiferae and Ardisia species

Jasamai M, Jalil J, Jantan I

Nat Prod Res, 2015;29(11):1055-8.
PMID: 25332053 DOI: 10.1080/14786419.2014.971317

A handful of bioactive compounds from plants have been reported to possess platelet-activating factor (PAF) antagonist activity. However, their mode of action is not well understood. Selected bioactive compounds that exhibit PAF antagonist activity and synthetic PAF antagonists were subjected to docking simulations using the MOE 2007.09 software package. The docking study of PAF antagonists was carried out on the PAF receptor (PAFR) protein which involves in various pathological responses mediated by PAF. The docking results revealed that amentoflavone (3) showed good interactions with the PAFR model where the flavone and phenolic moieties were mostly involved in these interactions. Knowledge on PAF antagonists' interactions with the PAFR model is a useful screening tool of potential PAF antagonists prior to performing PAF inhibitory assay.

Matched MeSH terms: Binding Sites
Molecular characterization, modeling and docking of CYP107CB2 from Bacillus lehensis G1, an alkaliphile

Ang SS, Salleh AB, Chor AL, Normi YM, Tejo BA, Rahman MB

Comput Biol Chem, 2015 Jun;56:19-29.
PMID: 25766878 DOI: 10.1016/j.compbiolchem.2015.02.015

Cytochrome P450s are a superfamily of heme monooxygenases which catalyze a wide range of biochemical reactions. The reactions involve the introduction of an oxygen atom into an inactivated carbon of a compound which is essential to produce an intermediate of a hydroxylated product. The diversity of chemical reactions catalyzed by cytochrome P450s has led to their increased demand in numerous industrial and biotechnology applications. A recent study showed that a gene sequence encoding a CYP was found in the genome of Bacillus lehensis G1, and this gene shared structural similarity with the bacterial vitamin D hydroxylase (Vdh) from Pseudonocardia autotrophica. The objectives of present study was to mine, for a novel CYP from a new isolate B. lehensis G1 alkaliphile and determine the biological properties and functionalities of CYP in this bacterium. Our study employed the usage of computational methods to search for the novel CYP from CYP structural databases to identify the conserved pattern, functional domain and sequence properties of the uncharacterized CYP from B. lehensis G1. A computational homology model of the protein's structure was generated and a docking analysis was performed to provide useful structural knowledge on the enzyme's possible substrate and their interaction. Sequence analysis indicated that the newly identified CYP, termed CYP107CB2, contained the fingerprint heme binding sequence motif FxxGxxxCxG at position 336-345 as well as other highly conserved motifs characteristic of cytochrome P450 proteins. Using docking studies, we identified Ser-79, Leu-81, Val-231, Val-279, Val-383, Ala-232, Thr-236 and Thr-283 as important active site residues capable of stabilizing interactions with several potential substrates, including vitamin D3, 25-hydroxyvitamin D3 and 1α-hydroxyvitamin D3, in which all substrates docked proximally to the enzyme's heme center. Biochemical analysis indicated that CYP107CB2 is a biologically active protein to produce 1α,25-dihydroxyvitamin D3 from 1α-hydroxyvitamin D3. Based on these results, we conclude that the novel CYP107CB2 identified from B. lehensis G1 is a putative vitamin D hydroxylase which is possibly capable of catalyzing the bioconversion of parental vitamin D3 to calcitriol, or related metabolic products.

Matched MeSH terms: Binding Sites
Synthesis, crystal structures and characterization of late first row transition metal complexes derived from benzothiazole core: anti-tuberculosis activity and special emphasis on DNA binding and cleavage property

Netalkar PP, Netalkar SP, Budagumpi S, Revankar VK

Eur J Med Chem, 2014 May 22;79:47-56.
PMID: 24721314 DOI: 10.1016/j.ejmech.2014.03.083

Air and moisture stable coordination compounds of late first row transition metals, viz. Co(II), Ni(II), Cu(II) and Zn(II), with a newly designed ligand, 2-(2-benzo[d]thiazol-2-yl)hydrazono)propan-1-ol (LH), were prepared and successfully characterized using various spectro-analytical techniques. The molecular structures of the ligand and nickel complex were unambiguously determined by single-crystal X-ray diffraction method. The [Ni(LH)2]Cl2.3H2O complex is stabilized by intermolecular CH⋯π stacking interactions between the methyl hydrogen and the C18 atom of the phenyl ring (C11-H11B⋯C18) forming 1D zig-zag chain structure. Both, the ligand and its copper complex, were electrochemically active in the working potential range, showing quasi-reversible redox system. The interactions of all the compounds with calf thymus DNA have been comprehensively investigated using electronic absorption spectroscopy, viscosity, electrochemistry and thermal denaturation studies. The cleavage reaction on pBR322 DNA has been monitored by agarose gel electrophoresis. The results showed that the ligand can bind to CT-DNA through partial intercalation, whereas the complexes bind electrostatically. Further, [Ni(LH)2]Cl2.3H2O and [CuLCl(H2O)2] complexes in the series have high binding and cleavage affinity towards pBR322 DNA. Additionally, all the compounds were screened for anti-tuberculosis activity. All the complexes revealed an MIC value of 0.8 μg/mL, which is almost 8 times active than standard used (Streptomycin, 6.25 μg/mL).

Matched MeSH terms: Binding Sites
Crystal structure of truncated haemoglobin from an extremely thermophilic and acidophilic bacterium

Jamil F, Teh AH, Schadich E, Saito JA, Najimudin N, Alam M

J. Biochem., 2014 Aug;156(2):97-106.
PMID: 24733432 DOI: 10.1093/jb/mvu023

A truncated haemoglobin (tHb) has been identified in an acidophilic and thermophilic methanotroph Methylacidiphilium infernorum. Hell's Gate Globin IV (HGbIV) and its related tHbs differ from all other bacterial tHbs due to their distinctively large sequence and polar distal haem pocket residues. Here we report the crystal structure of HGbIV determined at 1.96 Å resolution. The HGbIV structure has the distinctive 2/2 α-helical structure with extensions at both termini. It has a large distal site cavity in the haem pocket surrounded by four polar residues: His70(B9), His71(B10), Ser97(E11) and Trp137(G8). This cavity can bind bulky ligands such as a phosphate ion. Conformational shifts of His71(B10), Leu90(E4) and Leu93(E7) can also provide more space to accommodate larger ligands than the phosphate ion. The entrance/exit of such bulky ligands might be facilitated by positional flexibility in the CD1 loop, E helix and haem-propionate A. Therefore, the large cavity in HGbIV with polar His70(B9) and His71(B10), in contrast to the distal sites of other bacterial tHbs surrounded by non-polar residues, suggests its distinct physiological functions.

Matched MeSH terms: Binding Sites

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