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At least 199 records · Page 11Linked to original sources
PubMed2003

Structural adaptability in the ligand-binding pocket of the ecdysone hormone receptor.

The ecdysteroid hormones coordinate the major stages of insect development, notably moulting and metamorphosis, by binding to the ecdysone receptor (EcR); a ligand-inducible nuclear transcription factor. To bind either ligand or DNA, EcR must form a heterodimer with ultraspiracle (USP), the homologue of retinoid-X receptor. Here we report the crystal structures of the ligand-binding domains of the moth Heliothis virescens EcR-USP heterodimer in complex with the ecdysteroid ponasterone A and with a non-steroidal, lepidopteran-specific agonist BYI06830 used in agrochemical pest control. The two structures of EcR-USP emphasize the universality of heterodimerization as a general mechanism common to both vertebrates and invertebrates. Comparison of the EcR structures in complex with steroidal and non-steroidal ligands reveals radically different and only partially overlapping ligand-binding pockets that could not be predicted by molecular modelling and docking studies. These findings offer new perspectives for the design of insect-specific, environmentally safe insecticides. The concept of a ligand-dependent binding pocket in EcR provides an insight into the moulding of nuclear receptors to their ligand, and has potential applications for human nuclear receptors.

Animals↗
PubMed2006

Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis.

In this study, the synthesis and biological evaluation of heteroaryl-substituted dihydronaphthalenes and indenes (1-16) is described. The compounds were tested for activity by use of human CYP11B2 expressed in fission yeast and V79 MZh cells and for selectivity by use of human CYP11B1, CYP17, and CYP19. The most active inhibitor was the 6-methoxydihydronaphthalene 4 (IC(50) = 2 nM), showing a K(i) value of 1.3 nM and a competitive type of inhibition. The 5-methoxyindene 3 was found to be the most selective CYP11B2 inhibitor (IC(50) = 4 nM; CYP11B1 IC(50) = 5684 nM), which also showed only marginal inhibition of human CYP3A4 and CYP2D6. Docking and molecular dynamics studies using our homology-modeled CYP11B2 structure were performed to understand some structure-activity relationships. Caco-2 cell experiments revealed highly cell-permeable compounds, and metabolic studies with 4 using rat liver microsomes showed sufficient stability.

Animals↗
PubMed2004

Comparative analysis of putative agonist-binding modes in the human A1 adenosine receptor.

A recent study reported a model of the human A(1) adenosine receptor and its agonist binding site, proposing two putative binding modes in the same binding site for the natural agonist, adenosine. The present work investigates the flexibility of this binding site by exhaustive exploration with the natural agonist and with three other adenosine derivatives: N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and 5'-N-ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for agonists that would explain the role in the binding process of the different substitutions allowed at the 2, N6, and 5' positions of adenosine. This problem was addressed through docking simulations, molecular dynamics studies, and estimations of the ligand-binding free energy with both the AUTODOCK scoring function and the linear interaction energy (LIE) approach. The results point to a single receptor-binding position that explains the effects of the different chemical modifications on the adenosine derivatives considered here.

Adenosine↗
PubMed2005

Heteroaryl-substituted naphthalenes and structurally modified derivatives: selective inhibitors of CYP11B2 for the treatment of congestive heart failure and myocardial fibrosis.

Recently we proposed inhibition of aldosterone synthase (CYP11B2) as a novel strategy for the treatment of congestive heart failure and myocardial fibrosis. In this study the synthesis and biological evaluation of heteroaryl-substituted naphthalenes and quinolines (1-31) is described. Key step for the preparation of the compounds was a Suzuki cross-coupling. Activity of the compounds was determined in vitro using human CYP11B2 and selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. A large number of highly active and selective inhibitors of CYP11B2 was identified. The most active inhibitor was the 6-cyano compound 8 (IC50 = 3 nM) showing a competitive type of inhibition (K(i) value = 1.9 nM). The 6-ethoxy derivative 5 was found to be the most selective CYP11B2 inhibitor (IC50 = 12 nM; K(i) value = 8 nM; CYP11B1 IC50 = 5419 nM; selectivity factor = 451), showing no inhibition of human CYP3A4 (50 nM) and CYP2D6 (20 nM). Docking and molecular dynamics studies using our homology modeled CYP11B2 structure with selected compounds were performed. Caco-2 cell experiments revealed a large number of medium and highly permeable compounds and metabolic studies with 2 using rat liver microsomes showed sufficient stability.

Aromatase↗
PubMed2026

Inhibitory mechanism of anthocyanin B-ring substituents on advanced glycation end-product formation through bovine serum albumin binding: Insights from multispectral, molecular docking and proteomics approaches.

This study demonstrated that the inhibitory effect of anthocyanins on AGEs formation is highly dependent on the substitution pattern of the B-ring. Among the four anthocyanins, delphinidin-3-O-glucoside (D3G) exhibited the most potent antiglycation activity across BSA-fructose, MGO, and GO models with half-maximal inhibitory concentration (IC50) of 30.77, 200.29 and 269.97 μM. This superior performance was attributed to the presence of three hydroxyl groups on the B-ring, which facilitates a high-affinity, spontaneous binding interaction with BSA primarily through hydrophobic forces and hydrogen bonding. Spectroscopic and computational analyses revealed that D3G effectively stabilizes the protein scaffold, specifically recovering α-helix content and shielding critical subdomains (IB, IIA, and IIIA). Proteomics data are consistent with a protective binding mechanism, suggesting that D3G reduces the accessibility of key lysine and arginine residues to glycation-induced modifications. These findings provide a structural basis for developing D3G-rich extracts as targeted, structure-based functional ingredients to mitigate glycation-associated food quality degradation and related health issues.

Anthocyanins↗
PubMed2003

Molecular evaluation using in silico protein interaction profiles.

MOTIVATION: To find a correlation between the activities and structures of molecules is one of the most important subjects for molecular evaluation study. Traditional quantitative structure-activity relationship (QSAR) methodologies represent those attempts using physicochemical descriptors. Creating a new molecular description factor based on the results of a computational docking study will add new dimensions to molecular evaluation. RESULTS: We propose a new molecular description factor analysis system called the Comparative Molecular Interaction Profile Analysis (CoMIPA) system in which the AutoDock program is used for docking evaluation of small molecule compound-protein complexes. Interaction energies are calculated, and the data sets obtained are called interaction profiles (IPFs). Using the IPF as a scoring indicator, the system could be a powerful tool to cluster the interacting properties between small molecules and bio macromolecules such as ligand-receptor bindings. Further development of the system will enable us to predict the adverse effects of a drug candidate.

Algorithms↗
PubMed2005

A structural study towards the understanding of the interactions of SoxY, SoxZ, and SoxB, leading to the oxidation of sulfur anions via the novel global sulfur oxidizing (sox) operon.

Microbial redox reactions of inorganic sulfur compounds, mainly the sulfur anions, are one of the vital reactions responsible for the environmental sulfur balance. These reactions are mediated by phylogenetically diverse prokaryotes, which also take part in the extraction of metal ions from their sulfur containing ores. The sulfur oxidizing gene cluster (sox) of alpha-Proteobacteria comprises of at least 16 genes, forming two transcriptional units, viz., soxSRT and soxVWXYZABCDEFGH. SoxY is known to be a sulfur covalently binding protein, which binds sulfur anions (such as sulfate) to form SoxY-thiocysteine-S-sulfate, the first covalently bound sulfur adduct in the novel global sulfur anion oxidation cycle. SoxZ, a sulfur compound chelating protein, binds to SoxY forming a complex to which SoxB, a sulfate thiol-esterase, binds and ultimately cleaves the sulfur adduct. We employed homology modeling to construct the three-dimensional structures of the SoxY, SoxZ, and SoxB from Paracoccus pantotrophus. With the help of docking and molecular dynamics studies we have identified the residues of SoxY, SoxZ, and SoxB involved in the interaction. The probable mechanisms of the binding of SoxY with sulfate as well as the removal of sulfate from the SoxYZ complex are also established. Our study provides a rational basis to illustrate the molecular mechanism of the biochemistry of sulfur anion oxidation reactions by these industrially important organisms.

Alphaproteobacteria↗
PubMed1997

Probing the substrate specificity for lipases. II. Kinetic and modeling studies on the molecular recognition of 2-arylpropionic esters by Candida rugosa and Rhizomucor miehei lipases.

Racemic arylpropionic esters 1-3, precursors of therapeutically important non-steroidal antiinflammatory drugs, were subjected to hydrolyses in the presence of either Candida rugosa or Rhizomucor miehei crude lipases. The hydrolyses of 1 and 2 proved to be highly enantioselective, whereas 3 was not transformed at all. Both the substrate specificity and the enantioselectivity of these lipases were explained through a molecular modeling study involving docking experiments between 1-3 and the amino acids forming the enzymes active-sites, whose three dimensional structures were obtained from X-ray crystallographic data, followed by extensive conformational analysis on their computer-generated complexes. The results of this study also account for the high enantioselective and good yielding hydrolysis of 3 (as the corresponding 2-chloroethyl ester) catalyzed by CRL pretreated with 2-propanol, recently reported in the literature, and lead to admit that such a treatment may operate very deep conformational changes on the amino acids of the enzyme active-site.

Binding Sites↗
PubMed2006

Recognition profile of Morus nigra agglutinin (Morniga G) expressed by monomeric ligands, simple clusters and mammalian polyvalent glycotopes.

The carbohydrate binding properties of a novel member of the subfamily of galactose-specific jacalin-related lectin isolated from the bark of black mulberry (Morus nigra) (Morniga G) was studied in detail by enzyme-linked lectinosorbent and inhibition assays using panels of monomeric saccharides, mammalian polyvalent glycotopes and polysaccharides. Among the natural glycans tested for lectin binding, Morniga G reacted best with glycoproteins (gps) presenting a high density of tumor-associated carbohydrate antigens Tn (GalNAcalpha1-Ser/Thr) and Talpha (Galbeta1-3GalNAcalpha1-). Their reactivities, on a nanogram basis, were up to 72.5, 3.9x10(3), 6.0x10(3), 8.8x10(3) and 2.9x10(4) times higher than that of Tn-containing glycopeptides (M.W.<3000 Da), monomeric T, Tn, GalNAc and Gal, respectively. It also reacted well with many multi-antennary N-glycans with II (Galbeta1-4GlcNAc) termini, ABH histo-blood group antigens and their precursors containing high densities of I/II and T/Tn glycotopes, and sialylated T/Tn. Among the mono-, di- and oligosaccharides tested, Thomsen-Friedenreich (T) disaccharide with aromatic aglycon [Galbeta1-3GalNAcalpha1-benzyl (Talpha1-benzyl)] and Tn glycopeptides were the best inhibitors. Molecular modeling and docking studies indicated the occurrence of a primary GalNAcalpha1- and Galbeta1-3GalNAc glycotope-binding site in Morniga G. Using a recently proposed system [Wu, A.M., 2003. Carbohydrate structural units in glycoproteins and polysaccharides as important ligands for Gal and GalNAc reactive lectins. J. Biomed. Sci. 10, 676-688], the binding properties of the combining sites of Morniga G can be defined as follows: (i) the monosaccharide specificity is GalNAc/Gal>>Man/Glc, GlcNAc and lFuc; (ii) the mammalian glycotope specificity is Talpha1-benzyl>T>Tn>GalNAcbeta1-3Gal (P), while B/E (Galalpha1-3/4Gal), I/II (Galbeta1-3/4GlcNAc), S (GalNAcbeta1-4Gal), F/A (GalNAcalpha1-3GalNAc/Gal) and L (Galbeta1-4Glc) are inactive; (iii) the most active ligand is T/Tn; (iv) simple clustered Tn or triantennary N-glycans with II termini (Tri-II) have limited impact; (v) high-density polyvalent glycotopes play a prominent role for enhancing Morniga G reactivity. These results provide evidence for the binding of this lectin to dense cell surface T/Tn glycoconjugates and facilitate future usage of this lectin in biotechnological and medical applications.

Animals↗
PubMedDate not supplied

Binding of fatty acids to beta-cryptogein: quantitative structure-activity relationships and design of selective protein mutants.

Binding of fatty acids to cryptogein, the proteinaceous elicitor from Phytophthora, was studied by using molecular docking and quantitative structure-activity relationships analysis. Fatty acids bind to the groove located inside the cavity of cryptogein. The structure-activity model was constructed for the set of 27 different saturated and unsaturated fatty acids explaining 87% (81% cross-validated) of the quantitative variance in their binding affinity. The difference in binding between saturated and unsaturated fatty acids was described in the model by three electronic descriptors: the energy of the lowest unoccupied molecular orbital, the energy of the highest occupied molecular orbital, and the heat of formation. The presence of double bonds in the ligand generally resulted in stronger binding. The difference in binding within the group of saturated fatty acids was explained by two steric descriptors, i.e., ellipsoidal volume and inertia moment of length, and one hydrophobicity descriptor, i.e., lipophility. The developed model predicted strong binding for two biologically important molecules, geranylgeranyol and farnesol playing an important role in plant signaling as lipid anchors of some membrane proteins. Elicitin mutants selectively binding only one type of ligand were designed for future experimental studies.

Algal Proteins↗
PubMed2006

Steric interactions and the activity of fentanyl analogs at the mu-opioid receptor.

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in the attempt to develop highly selective mu-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking in a study of the formation of complexes between a series of active fentanyl analogs and the mu-opioid receptor is described. The optimal position and orientation of fourteen fentanyl analogs in the binding pocket of the mu-receptor were determined. The major receptor amino acids and the ligand functional groups participating in the complex formation were identified. Stereochemical effects on the potency and binding are explained. The proposed model of ligand-receptor binding is in agreement with point mutation experiments explaining the role of the amino acids: Asp147, Tyr148, Asn230, His297, Trp318, His319, Cys321, and Tyr326 in the complex formation. In addition, the following amino acids were identified as being important for ligand binding or receptor activation: Ile322, Gly325, Val300, Met203, Leu200, Val143, and Ile144.

Binding Sites↗
PubMed2006

Novel tight binding PETT, HEPT and DABO-based non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are a key component of effective combination antiretroviral therapies for HIV/AIDS. NNRTIs despite their chemical diversity, bind to a common allosteric site of HIV-1 RT, the primary target for anti-AIDS chemotherapy, and noncompetitively inhibit DNA polymerization. NNRTIs currently in clinical use have a low genetic barrier to resistance and therefore, the need for novel NNRTIs active against drug-resistant mutants selected by current therapies is of paramount importance. We describe the chemistry and biological evaluation of highly potent novel phenethylthiazolylthiourea (PETT), 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the hydrophobic binding pocket of HIV-1 RT. These NNRTIs were rationally designed by molecular modeling and docking studies using a novel composite binding pocket that predicted how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up and how these changes could affect NNRTI binding. Several ligand derivatization sites were identified for docked NNRTIs that fit the composite binding pocket. The best fit was determined by calculating an inhibition constant (Ludi Ki) of the docked compound for the composite binding pocket. Compounds with a Ludi Ki of <1 microM were identified as the most promising tight binding NNRTIs. These NNRTIs displayed high selective indices with robust anti-HIV-1 activity against the wild-type and drug-resistant isolates carrying multiple RT gene mutations. The high rate of treatment failure due to the emergence of drug resistance mutations makes the discovery of broad-spectrum PETT, HEPT and DABO-based NNRTIs useful as a component of effective combination regimens.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site.

The present work describes the building of a human A(1) adenosine receptor (hA(1)AR) model, based on the X-ray crystal structure of bovine rhodopsin, and its use as a basis for the investigation of some important structural characteristics of the receptor. One of the issues investigated was the protonation position of two histidine residues known to influence ligand binding, with protonation of His251 (6.52) in epsilon position and His278 (7.43) in delta position showing the best agreement with experimental evidence. The model was also used to study the position and structural role of water molecules present in the helical bundle. Finally, the binding site location and the ligand docking were investigated using an objective strategy. A suitable site for the binding of the ribose moiety of adenosine was first postulated and further confirmed by means of a novel chemometric strategy based on GRIND descriptors. Using this position as an anchor point, the binding of adenosine was studied by docking and molecular dynamics simulations obtaining two putative binding positions in good agreement with experimental data.

Adenosine↗
PubMed2004

New 3-piperonylcoumarins as inhibitors of glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from Trypanosoma cruzi.

This article describes the synthesis and inhibitory activities of a series of new 3-piperonylcoumarins, designed as inhibitors of glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from Trypanosoma cruzi. The design was based on the structures of previously identified natural products hits. The most active synthesized derivatives contain heterocyclic rings at position 6. SAR studies, performed by electronic indices methodology (EIM), clustered the molecules in different groups due to the chemical substitutions regarding the biological activity. Molecular modeling studies by docking suggested a different binding mode for the most active derivatives, when compared to natural hit chalepin. Moreover, the coumarin ring seems to act only as a spacer group.

Animals↗
PubMed1999

Protease-catalyzed hydrolysis of substrate mimetics (inverse substrates): A new approach reveals a new mechanism.

Contrary to common protease substrates, the hydrolysis of 4-guanidinophenyl esters of the Boc-Xaa-OGp type by trypsin and trypsin-like proteases performs easily and independently of the structure and chirality of the acyl moiety. The hydrolysis of this new class of substrate mimetics, previously called inverse substrates, is enabled by the highly specific leaving group. However, the mechanism cannot be explained on the basis of the conventional binding model which defines the interactions between the protease and its substrate. Hydrolysis and aminolysis kinetics, protein-ligand docking, and molecular dynamics studies have been carried out in order to get insight into the catalytic mechanism which holds for these substrate mimetics. The experimental and theoretical results obtained for the serine protease trypsin suggest a novel extended kinetic model. It explains the hydrolysis of these types of protease substrates and accounts for the structural consequences for their aminolysis.

Catalysis↗
PubMed2005

Development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). Rational design of novel, selective, and highly potent BuChE inhibitors.

Tacrine heterobivalent ligands were designed as novel and reversible inhibitors of cholinesterases. On the basis of the investigation of the active site gorge topology of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) and by using flexible docking procedures, molecular modeling studies formulated the hypothesis of extra interaction sites in the active gorge of hBuChE, namely, a mid-gorge interaction site and a peripheral interaction site. The design strategy led to novel BuChE inhibitors, balancing potency and selectivity. Among the compounds identified, the heterobivalent ligand 4m, containing an amide nitrogen and a sulfur atom at the 8-membered tether level, is one of the most potent and selective BuChE inhibitors described to date. The novel inhibitors, bearing postulated key features, validated the hypothesis of the presence of extra interaction sites within the hBuChE active site gorge.

Acetylcholinesterase↗
PubMed2000

Nonconventional amide bond formation catalysis: programming enzyme specificity with substrate mimetics.

This article reports on the design and characteristics of substrate mimetics in protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide synthesis and the general advantages of substrate mimetics over common acyl donor components are described. The binding behavior of these artificial substrates and the mechanism of catalysis are further discussed on the basis of hydrolysis, acyl transfer, protein-ligand docking, and molecular dynamics studies on the trypsin model. The general validity of the substrate mimetic concept is illustrated by the expansion of this strategy to trypsin-like, glutamic acid-specific, and hydrophobic amino acid-specific proteases. Finally, opportunities for the combination of the substrate mimetic strategy with the chemical solid-phase peptide synthesis and the use of substrate mimetics for non-peptide organic amide synthesis are presented.

Acyltransferases↗