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At least 199 records · Page 11Linked to original sources

PubMed1998

Molecular modeling study of tubulosine and other related ipecac alkaloids.

A molecular modeling study of two alkaloids, tubulosine and psychotrine, isolated from the sap of Pogonopus speciosus, and other related ipecac alkaloids, showed that these flexible alkaloids favor a nonplanar structure. The biologically active compounds had conformations with a similar angle between aromatic ring A, the nitrogen in ring B, and ring D. This angle was related to the biological activity reported for these compounds. Our results support the hypothesis of two different types of receptor interactions, one for the nonplanar compounds and another for the planar compounds.

Alkaloids↗

PubMed1991

Molecular modelling of bacterial deep rough mutant lipopolysaccharide of Escherichia coli.

Molecular modelling techniques have been applied to compute the conformation accessible to bacterial deep rough lipopolysaccharide of Escherichia coli (Re-LPS). Analyses of the results showed that the models typically exhibit a tilt of the diglucosamine backbone with respect to the membrane normal of 53 +/- 7 degrees while both the glucosamine ring planes are oriented approximately parallel to the membrane normal. Different models were found to show compact and elongated types of acyl chain arrangements, both producing anisotropic lateral dimensions of the models of 1.0-1.1 nm and 1.7-2.0 nm for the shorter and the longer side, respectively. The conformationally allowed range of the isolated dOclA(alpha-2-4)dOclA disaccharide (dOclA = 3-deoxy-D-mannooctulosonic acid) was found to be extremely limited. It appeared that the dOclA disaccharide (dOclA)2 is centred at the top of the Re-LPS molecule preferring two orientations stabilized by hydrogen bonds involving only one phosphate group of the lipid A moiety at a time. The effect of charges on the Re-LPS conformations has been studied in separate calculations. From these calculations it was obvious that charges have no significant effects on the conformations of the isolated lipid A and (dOclA)2 moieties. However, it was found that the orientation of (dOclA)2 with respect to the lipid A part is highly sensitive to charges, i.e. in the charged models the proximity of phosphate and carboxyl groups is prevented by strong electrostatic repulsion between these negatively charged groups. In order to rationalize the acyl chain packing of the models, a simple geometrical model which correlates the tilt of the diglucosamine backbone with the energically favoured close packing of the acyl chains is proposed. Furthermore, the possibility of a chelate-like complexation of divalent cations and its contribution to head group mobility is discussed.

Escherichia coli↗

PubMed1997

Molecular modeling of mechanotransduction in the nematode Caenorhabditis elegans.

Genetic and molecular studies of touch avoidance in the nematode Caenorhabditis elegans have resulted in a molecular model for a mechanotransducing complex. mec-4 and mec-10 encode proteins hypothesized to be subunits of a mechanically gated ion channel that are related to subunits of the vertebrate amiloride-sensitive epithelial Na+ channel. Products of mec-5, a novel collagen, and mec-9, a protein that includes multiple Kunitz-type protease inhibitor repeats and EGF repeats, may interact with the channel in the extracellular matrix. Inside the cell, specialized 15-protofilament microtubules composed of mec-12 alpha-tubulin and mec-7 beta-tubulin may be linked to the mechanosensitive channel by stomatin-homologous MEC-2. MEC-4 and MEC-10 are members of a large family of C. elegans proteins, the degenerins. Two other degenerins, UNC-8 and DEL-1, are candidate components of a stretch-sensitive channel in motor neurons. Implications for advancing understanding of mechanotransduction in other systems are discussed.

Animals↗

PubMed1994

Conformational analysis, molecular modeling, and quantitative structure-activity relationship studies of agents for the inhibition of astrocytic chloride transport.

Molecular modeling studies were carried out on a series of 1-oxoisoindolines which are pharmacologically active as inhibitors of astrocytic chloride transport. Conformational analysis revealed that the halogen substituent exerted a pronounced steric directing effect on the acid side chain. The 4-substituted analogs apparently provided for the best spatial arrangement of pharamacophoric elements of the molecules. Conventional quantitative structure-activity relationship (QSAR) studies using lipophilic and dipole moment characteristics of the molecules as physical descriptor variables in the regression equation yielded a statistically significant model. Comparative molecular field analysis (CoMFA) was utilized as a three-dimensional QSAR technique to explore changes in the steric and electrostatic fields of the molecules that can account for differences in biological activity values. A highly predictive model was attained which supported the results from the qualitative and conventional quantitative structure-activity relationship analyses. These modeling techniques represent the evolutionary process by which structure-activity methods were employed to aid in the development of novel more potent inhibitors of astrocytic chloride transport.

Astrocytes↗

PubMed1996

Structure/activity relationships of polyfunctional diterpenes of the tigliane type. A pharmacophore model for protein-kinase-C activators based on structure/activity studies and molecular modeling of the tumor promoters 12-O-tetradecanoylphorbol 13-acetate and 3-O-tetradecanoylingenol.

For protein kinase C (PKC), a family of isoenzymes with serine/threonine-kinase activity identified as the major cellular receptor for certain skin irritants and tumor promoters, a new pharmacophore model is presented. By structure/activity relationship studies of naturally occurring and synthetic diterpene esters of the tigliane type (PKC activators) it is demonstrated that in addition to the oxygen at C20 it is the O-acyl function in position C13 which is critically essential for skin-irritant and tumor-promoting bioactivities rather than other oxygen atoms. This result is confirmed and extended by computer-assisted molecular modeling of tigliane-type and ingenane-type tumor promoters. It is contrasted to certain features attributed to the pharmacophore based upon the recently determined crystallographic structure of the effector-binding domain Cys2 of PKC delta complexed with the pseudo-agonist phorbol 13-acetate.

Animals↗

PubMed1988

A molecular model for proflavine-DNA intercalation.

A molecular model has been derived for the intercalation of proflavine into the CpG site of the decamer duplex of d(GATACGATAC). The starting geometry of the intercalation site was taken from previous crystallographic studies on the d(CpG)-proflavine complex, and molecular mechanics used to obtain a stereochemically acceptable structure. This has widened grooves compared to standard A- or B- double helices, as well as distinct conformational, roll, twist and tilt features.

Acridines↗

PubMed1997

The cannabinoid receptor: computer-aided molecular modeling and docking of ligand.

A three-dimensional model of human cannabinoid receptor is constructed using computer-aided molecular modeling techniques. The helices of bacteriorhodopsin were used as the initial template to construct the transmembrane helices. The extracellular and intracellular loops were added using the SYBYL molecular modeling package. The extracellular N terminus was modeled on the basis of its similarity to rat oncomodulin. Similarly, the C terminus was constructed on the basis of similarity to bovine prothrombin fragment 1. The final structure was refined by several runs of minimization and dynamics calculation using the CHARMm package. delta 9-Tetra hydrocannabinol was docked into the internal cavity using the AUTODOCK program. Our study snows that there may be a calcium-binding site in the extracellular N terminus of this receptor. The ligand binds mainly to a hydrophobic site, which consists of residues Met-240, Trp-241 (TMH-4), Trp-356, Leu-359, Leu-360 (TMH-6), and Ala-283 (TMH-5). Its phenolic hydroxyl group forms a hydrogen bond with the carboxy group of Ala-198 (TMH-3). The results of modeling agree well with experimental QSAR studies.

Amino Acid Sequence↗

PubMed1987

Towards an identification of the pyrethroid pharmacophore. A molecular modelling study of some pyrethroid esters.

A molecular modelling and computer graphics study of a series of pyrethroid insecticides has been carried out. The three-dimensional arrangement of the groups essential for the biological activity (pharmacophore) has been identified for the acid and the alcohol moieties, respectively. These pharmacophores are based on the relationship between molecular structure and biological activity for a number of pyrethroid esters. The pharmacophores, which describe the relative location in space of the unsaturated systems, the dimethyl groups and the ester moiety, may be useful in the design of novel compounds with pyrethroid activity.

Binding Sites↗

PubMed2000

Molecular modeling of mammalian cytochromes P450: application to study enzyme function.

Cytochromes P450 are important heme-containing enzymes that catalyze the oxidation of a vast array of endogenous and exogenous compounds, including drugs and carcinogens. One of the more successful approaches to study P450 function involves molecular modeling. Because none of the mammalian P450s have been crystallized, a number of homology models have been constructed based on the structures of known bacterial P450s. Molecular models, generated using molecular replacement or distance geometry methods, can be used to dock substrates and/or inhibitors in the active site to explain various aspects of enzyme function. The majority of modeling research has dealt with enzyme-substrate interactions in the active site. The analysis of these interactions has helped us to better understand the mechanism of P450 catalysis and provided the structural basis for the regio- and stereospecificity of substrate oxidation as well as susceptibility to inhibition or inactivation. The models have been utilized to identify and/or confirm key residues and to rationally interpret experimental data. The alteration in activity in a mutant P450 can be related to changes in enzyme-substrate/inhibitor interactions, such as the removal or appearance of van der Waals overlaps or changes in compound mobility. Homology models can also help to analyze P450-redox partner interactions and identify critical determinants of protein stability. We can expect further development of molecular modeling methods and their increasing contribution into research on P450 function as an integral part of a combined theoretical-experimental approach.

Amino Acid Sequence↗

PubMed1989

Three-dimensional steric molecular modeling of the 5-hydroxytryptamine3 receptor pharmacophore.

A computer-based three-dimensional steric molecular model of the 5-hydroxytryptamine3 (5-HT3) receptor pharmacophore was defined on the basis of radioligand binding data. Analysis of published data led to the identification of 19 different chemical structures that share only a single known pharmacological property, i.e., less than 10 nM affinity for the 5-HT3 receptor. These 19 compounds were then categorized into seven chemical families, which derive from six main steric "core" structures. From the composite analysis of all 19 potent agents, nine steric chemical criteria were derived, which can be used to describe the 5-HT3 receptor pharmacophore. This information was then used to explain the 5-HT3 receptor inactivity of atrophine, a compound that differs structurally from ICS 205-930 in the steric properties of only a single key atom. The steric chemical information was also used to predict the activity of serotonergic compounds that had never been analyzed at 5-HT3 receptor binding sites. Two serotonergic drugs that meet all nine steric criteria were found to be active at the 5-HT3 receptor binding site (i.e., pizotifen, KI = 42 +/- 10 nM, and clozapine, KI = 52 +/- 8 nM). By contrast, two serotonergic agents that do not meet the criteria were found to be inactive at the 5-HT3 receptor binding site (i.e., ipsapirone and pirenperone, KI values greater than 1000 nM). This computer-based steric molecular modeling approach allows for the analysis and identification of 5-HT3 receptor-active agents with minimal dependence upon animals and radioactive compounds.

Animals↗

PubMed1995

The substrate binding site of human liver cytochrome P450 2C9: an approach using designed tienilic acid derivatives and molecular modeling.

Biochemical experiments, using the well-defined human liver CYP2C9 expressed in yeast, and molecular modeling techniques were used to derive a predictive model for substrates of CYP2C9. The ability of 10 2-aroylthiophenes related to tienilic acid to act as substrates for CYP2C9 was studied. Four of them were original compounds that were synthesized and completely characterized by several spectroscopic techniques. In these 10 compounds various chemical functions, such as ester, amide, alcohol, phenol, ether or tetrazole functions, replaced the OCH2COOH function of tienilic acid. Among them, only the derivatives containing an acidic function (carboxylic acids, phenol, and tetrazole whose pKaS are 4.8, 6.3, and 3.8, respectively) underwent a 5-hydroxylation of their thiophene ring like tienilic acid. Despite their close structural analogy with tienilic acid, all of the other compounds not only did not undergo any 5-hydroxylation of their thiophene ring but also failed to act as inhibitors of CYP2C9. These results strongly suggested that the presence, at pH 7.4, of a negative charge on the substrate is a very important feature in its recognition by CYP2C9. In fact, the four new substrates of CYP2C9 described in this study, a carboxylic acid, phenol, and tetrazole derivative, each of which is related to tienilic acid, and the antiinflammatory drug, suprofen (with Km between 12 and 130 microM and kcat between 0.2 and 1.3 min-1), as well as almost all CYP2C9 substrates reported in the literature, exhibit a pKa below 7 (except phenytoin whose pKa is 8.1). They mainly exist as anions at physiological pH. By using molecular modeling techniques, 12 CYP2C9 substrates were superimposed with respect to their hydroxylation site and fitted onto templates, which were rigid molecules such as (S)-warfarin and phenytoin. It was thus possible to arrange them in order that all their anionic sites were at a distance around 4 A from a common point (a putative cationic site of the protein) in space. These results provide a model of the substrate binding site of CYP2C9, in which substrates interact through their anionic site A- with a cationic residue of the CYP2C9 protein C+. In that model, the distance between the hydroxylation site (Hy) and the anionic site (A-) is 7.8 +/- 1.6 A, and the <HyA-C+ angle is 82 +/- 15 degrees.

Aryl Hydrocarbon Hydroxylases↗

PubMed1991

Effects of gene mutations in lipoprotein and hepatic lipases as interpreted by a molecular model of the pancreatic triglyceride lipase.

A molecular model of human pancreatic lipase (Winkler, F. K., D'Arcy, A., and Hunziker, W. (1990) Nature 343, 771-774) is used to explain the possible structural effects of the amino acid mutations identified to date in the human lipoprotein and hepatic lipase genes. A sequence homology profile was used to evaluate the alignment of the amino acid sequences of all three lipolytic enzymes (Kirchgessner, T. G., Chuat, J.-C., Heinzmann, C., Etienne, J., Guilhot, S., Svenson, K., Ameis, D., Pilon, C., D'Auriol, L., Andalibi, A., Schotz, M. C., Galibert, F., and Lusis, A. J. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 9647-9651) with respect to the secondary structure elements identified in the pancreatic lipase. As expected, maximum homology is observed in internal regions namely the hydrophobic strands of the central beta-pleated sheet. This observation strongly supports the hypothesis that all three molecules exhibit a very similar three-dimensional structure, particularly in the N-terminal catalytic domain. There is considerable variation in some of the surface loops connecting the individual strands, whereas others are conserved. It is hypothesized that the most conserved loops located around the active site are responsible for the catalytic function (similar for all three enzymes), whereas those that markedly differ are involved in the regulation at the molecular level, namely the binding of colipase (pancreatic enzyme) and apolipoprotein CII (lipoprotein lipase). The currently available library of hepatic and lipoprotein gene mutations seems to indicate that the majority of mutants disrupt the folding of the polypeptide chain, rather than affect specific constellations in and around the catalytic site or regulatory loops.

Amino Acid Sequence↗

PubMed1998

Structural and functional characterization of Streptomyces plicatus beta-N-acetylhexosaminidase by comparative molecular modeling and site-directed mutagenesis.

We have sequenced the Streptomyces plicatus beta-N-acetylhexosaminidase (SpHex) gene and identified the encoded protein as a member of family 20 glycosyl hydrolases. This family includes human beta-N-acetylhexosaminidases whose deficiency results in various forms of GM2 gangliosidosis. Based upon the x-ray structure of Serratia marcescens chitobiase (SmChb), we generated a three-dimensional model of SpHex by comparative molecular modeling. The overall structure of the enzyme is very similar to homology modeling-derived structures of human beta-N-acetylhexosaminidases, with differences being confined mainly to loop regions. From previous studies of the human enzymes, sequence alignments of family 20 enzymes, and analysis of the SmChb x-ray structure, we selected and mutated putative SpHex active site residues. Arg162 --> His mutation increased Km 40-fold and reduced Vmax 5-fold, providing the first biochemical evidence for this conserved Arg residue (Arg178 in human beta-N-acetylhexosaminidase A (HexA) and Arg349 in SmChb) as a substrate-binding residue in a family 20 enzyme, a finding consistent with our three-dimensional model of SpHex. Glu314 --> Gln reduced Vmax 296-fold, reduced Km 7-fold, and altered the pH profile, consistent with it being the catalytic acid residue as suggested by our model and other studies. Asp246 --> Asn reduced Vmax 2-fold and increased Km only 1.2-fold, suggesting that Asp246 may play a lesser role in the catalytic mechanism of this enzyme. Taken together with the x-ray structure of SmChb, these studies suggest a common catalytic mechanism for family 20 glycosyl hydrolases.

Amino Acid Sequence↗

PubMed2000

Sheep cytosolic branched-chain amino acid aminotransferase: cDNA cloning, primary structure and molecular modelling and its unique expression in muscles.

This paper presents the cloning and the molecular modelling of the cytosolic branched-chain amino acid aminotransferase (BCATc) from sheep brain. The sheep BCATc cDNA (3 kb) encodes a mature polypeptide of 385 amino acids with a calculated molecular mass of 43072.93 Da. The sequence of the sheep BCATc cDNA is more similar to other mammalian BCATc cDNAs (53-87% identical) than to the sheep mitochondrial branched-chain amino acid aminotransferase (52%). Sheep BCATc belongs to the IV Folding class of pyridoxal-5'-phosphate-depending enzymes. Based on the known structure of the branched-chain amino acid aminotransferase (BCAT) from Escherichia coli, a molecular model of sheep BCATc (amino acid residues 62-385) was built. This is the first three-dimensional model of any mammalian BCAT. It suggests that the enzymatic mechanism of sheep BCATc and likely of all mammalian BCAT is very similar to the mechanism of the E. coli BCAT and confirms the hypotheses regarding to the substrate binding sites of E. coli BCAT. Sheep skeletal muscle, which is the main in vivo site for transamination of branched-chain amino acids, exhibits an unique expression of BCATc.

Amino Acid Sequence↗

PubMed2006

Docking of human interleukin-15 to its specific receptor alpha chain: correlation between molecular modeling and mutagenesis experimental data.

A structural model of the sushi domain of IL-15Ralpha was first obtained by homology modeling to study its interactions with IL-15 by means of molecular modeling, peptide scanning, and site-directed mutagenesis. From these experimental data, a putative interacting surface of IL-15Ralpha with a previously published IL-15 model was inferred: Leu25, Leu44, and Glu46 of IL-15 and Arg35 of IL-15Ralpha were found to be key interfacial residues and were subsequently used as filters for the construction of docking solutions. Human IL-15/IL-15Ralpha complexes were constructed in two stages, with a preliminary docking procedure, treating the two partners as rigid bodies and using these filters. In this first stage, two classes of docking solutions were characterized. From a topological point of view, each solution could be derived from the other by reverse orientation of one partner in relation to the other. In a second stage, several further energy refinements clearly favored one solution. Moreover, this unique docking solution was confirmed by molecular modeling of IL-15 mutants previously built and tested in our laboratory. Finally, this complex model, which is a useful tool to study the IL-15/IL-15Ralpha interface, was topologically compared to IL-2/IL-2Ralpha complexes (previous model in the literature and recent crystal structure).

Amino Acid Sequence↗

PubMed1999

Identification of binding sites of bopindolol and its two metabolites with beta1-adrenoceptors by molecular modeling: comparison with beta2 adrenoceptors.

This study was designed to examine the importance of interaction in the bindings of nonselective beta-blockers to beta1-adrenoceptors (beta1-ARs) as compared with beta2-ARs, using molecular modeling. The beta-blockers used in this study were bopindolol [4-(benzoyloxy-3-t- butylaminopropyl)-2-methylindol hydrogen malomate], its two metabolites [18-502 - hydrolyzed bopindolol or 4-(3-t-butylamino-2-hydroxypropoxy)-2-methyl indole - and 20-785 - 4-(3-t-butylaminopropoxy)-2-carboxyl indole], and propranolol. Molecular modeling was performed on an Indigo2 workstation (Silicon Graphic) using Discover/Insight II (Molecular Simulations) software. Through molecular modeling, possible binding sites for these drugs were suggested to lie between helices 3, 4, 5, and 6 of the beta1-AR. The amine, benzoic acid, indole methyl, t-butyl, phenyl, and indole functional groups of bopindolol possibly interact with Asp138 (transmembrane - TM - 3), Ser190 (TM 4), Ala343 (TM 6), Val137 (TM 3), Pro339 (TM6), Cys336 (TM 4), Leu237 (TM 5), and Pro236 (TM 5) of beta1-AR, respectively, by either hydrogen bonding or hydrophobic interactions. In addition, 18-502, 20-785, and propranolol also interacted with sites at the same positions as those of beta2-ARs. Thus, the results of the present study suggested that although Ala343 and Val137 of beta1-AR among these amino acids were different from those of beta2-AR, the interactions at the same sites between ligands and amino acids of beta1-AR as those of beta2-ARs may occur because these drugs are nonselective.

Adrenergic beta-Antagonists↗

PubMed2000

Building three-dimensional structures of HIV-1 coreceptor CCR5 and its interaction with antagonist TAK779 by comparative molecular modeling.

AIM: To study the mechanism of interaction of CCR5 receptor with its antagonist TAK779. METHODS: Comparative molecular modeling has been used to develop the 3D-structural models of CCR5 receptor and its complex with TAK779. Molecular mechanics has been applied to optimize the above molecular models. Quantum mechanics has been utilized to calculate the structural information of TAK779. DOCK4.0 program is employed to dock the TAK779 molecular into the binding site of CCR5 receptor. RESULTS: The 3D-structural model of CCR5 receptor is constructed using the 3D-model of frog rhodopsin as a template. The binding pocket is situated in the transmembrane helices 3, 5, 6, and 7, and it is composed of conserved residues of Tyr108, Gly111, Ser114, Glu283, Gly286, and Cys290, and conservatively varied residues including Thr105, Leu107, Phe112, Gly115, Lys197, and Met287. O1, N7, N17, and O19 of TAK779 are the active center of TAK779. The pyran cycle and the aminium group of TAK779 interact with residues in the binding pocket of CCR5 receptor, the other part of TAK779 interacts with residues from the extracellular loops of CCR5. The binding energy of TAK779 with CCR5 is -51.606 kcal/mol. CONCLUSION: The model constructed and the interaction mode reported in the present study are useful in further understanding the molecular mechanism of receptor-virus recognition and designing new inhibitors of HIV-1 infection.

Amides↗

PubMed1995

Molecular modelling of members of the P4502A subfamily: application to studies of enzyme specificity.

1. Using the recently published crystal structure of a bacterial P450, namely 102 (also termed P450bm3), as a template molecular models of mammalian 2A1, 2A4, 2A5 and 2A6 were constructed. 2. Substrate interaction studies demonstrated that in keeping with known catalytic activities the putative binding sites of mouse hepatic P4502A4 and 2A5 oriented testosterone for 15 alpha-hydroxylation and coumarin for 7-hydroxylation respectively. 3. Substrate interaction studies with the putative binding site of human liver P4502A6 demonstrated that coumarin was oriented for 7-hydroxylation. However, in keeping with previous site-directed mutagenesis studies with P4502A4 and 2A5, changing a single phenylalanine residue to leucine in 2A6 gave rise to a mutant enzyme, which could bind testosterone as a substrate for 15 alpha-hydroxylation rather than coumarin. 4. Substrate interaction studies with the putative binding site of rat hepatic P4502A1 suggested that this isoenzyme would hydroxylate coumarin at the 3- rather than at the 7-position. 5. The results of these molecular modelling studies demonstrate that apparently minor modifications to P4502A subfamily amino acid sequences can result in major alterations in enzyme specificity. 6. Molecular modelling is thus a useful technique that can aid in elucidating substrate specificities of P450 isoenzymes and species differences in xenobiotic metabolism. The technique can also be utilized to complement site-directed mutagenesis studies in order to identify critical structural features of P450s and other enzymes.

Amino Acid Sequence↗