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Biomedical subjects

G H Loew

Publications and source records attributed to G H Loew.

At least 91 records · Page 5Linked to original sources
PubMed1986

Theoretical studies of cytochrome P-450. Characterization of stable and transient active states, reaction mechanisms and substrate-enzyme interactions.

The techniques of theoretical chemistry embodied in ab initio and semiempirical quantum mechanical and empirical energy methods have been used to elucidate the relationship between structure, spectra and function of the oxidative metabolizing heme proteins, the cytochrome P-450s, using a recent X-ray structure of a P-450cam-camphor complex. Specifically, the origin of the spin state changes when substrate binds to the oxidized resting state and the nature of the transient biologically active oxygen transfer state have been described. Mechanisms of hydroxylation and epoxidation, the two fundamental oxidative reactions performed by these enzymes, have been deduced and the role of substrate binding and orientation on product distribution investigated.

Binding Sites↗
PubMed1985

Base-pairing properties of O-methylated bases of nucleic acids. Energetic and steric considerations.

Base-pairing properties of O-methylated nucleic-acid bases have been systematically investigated using both semi-empirical quantum-mechanical methods and a second-order perturbation formalism. The energetic, steric and electronic properties of (a) the individual methylated bases, (b) possible base-pairs formed between O-methylated and normal bases, and (c) mini-helices incorporating O-methylated bases were calculated. Two types of base-paired complexes were obtained: Those involving classical linear hydrogen bonds, and those involving bifurcated hydrogen-donor-hydrogen-acceptor interactions. In most complexes the presence of mispairs in the helical structure of nucleic acids is expected to create a local perturbation in the structure of the helix. Even though the most stable planar configurations of the mispairs may deviate markedly from those in the regular double helix, the induced deformations in the structure of the backbone are relatively small. Internal energies and geometries of mispairs are strongly affected by the conformation of the exocyclic group of the methylated bases. Another important contribution to the stability of various base-pairing schemes comes from stacking interactions.

Allosteric Site↗
PubMed1985

Computer-assisted mechanistic structure-activity studies: application to diverse classes of chemical carcinogens.

In the first part of this paper we have indicated how the techniques and capabilities of theoretical chemistry, together with experimental results, can be used in a mechanistic approach to structure-activity studies of toxicity. In the second part, we have illustrated how this computer-assisted approach has been used to identify and calculate causally related molecular indicators of relative carcinogenic activity in five classes of chemical carcinogens: polycyclic aromatic hydrocarbons and their methyl derivatives, aromatic amines, chloroethanes, chloroalkenes and dialkyl nitrosamines. In each class of chemicals studied, candidate molecular indicators have been identified that could be useful in predictive screening of unknown compounds. In addition, further insights into some mechanistic aspects of chemical carcinogenesis have been obtained. Finally, experiments have been suggested to both verify the usefulness of the indicators and test their mechanistic implications.

Amines↗
PubMed1985

Theoretical structure-activity studies of beta-carboline analogs. Requirements for benzodiazepine receptor affinity and antagonist activity.

The techniques of theoretical chemistry have been used to elucidate the molecular properties and modes of receptor binding that modulate receptor affinity and antagonist activity of the beta-carbolines, a class of potent benzodiazepine antagonists. Six analogs were chosen in order to investigate the role of the amine (NH) group, the aromatic nitrogen, and the C3-substituent in determining receptor affinities. Electrostatic potential mapping and characterization of explicit drug-receptor interactions have led to the hypothesis that simultaneous interaction of a model cationic arginine site with the N2 and C3-substituents could play a key role in determining receptor affinities. The electron-withdrawing effects of C3-substituents on the amine nitrogen appear less important, though interactions of these groups with an anionic glutamate or aspartate site could also occur at the receptor. Similarly, stacking interactions with neutral or cationic aromatic residues such as tryptophan or protonated histidine could occur, but do not appear to be determinants of the relative receptor affinity of the beta-carbolines.

Anions↗
PubMed1985

Metabolic activation and toxicity of acetaminophen and related analogs. A theoretical study.

Reaction thermodynamics have been calculated for an oxene model for cytochrome P-450 oxidations of four related arylamines: aniline, p-hydroxyaniline, acetanilide, and acetaminophen, by both radical and nonradical mechanisms, using a semiempirical molecular orbital method (modified neglect of differential overlap). The results indicate that for both p-hydroxyaniline and acetaminophen, a recently proposed peroxidase-like mechanism leading directly to p-benzoquinoneimines via radical intermediates is thermodynamically favored over N-hydroxylamine formation by H abstraction or addition rearrangement. These studies also provide a detailed characterization of three candidate species for the toxic reactive intermediate of acetaminophen: 1) p-benzoquinoneimines, 2) the radical intermediate formed by H abstraction from the nitrogen, and 3) the radical intermediate formed by H abstraction from the phenol. Calculated electron and spin densities indicate that the radical formed by H abstraction from the phenol oxygen does not remain localized on the oxygen, but is primarily a semiquinone aryl radical with significant unpaired spin density on the ring carbon atoms, particularly on C-3 and C-5. This result is consistent with the hyperfine splitting pattern observed for a transient radical species in a hydroxyl radical-mediated chemical oxidation of acetaminophen. The radical formed by H abstraction from the nitrogen also delocalizes on the ring carbons, but to a lesser extent and at the 2- and 4-positions. A closed shell mechanism of N oxidation of arylamines appears to lead directly to the hydroxylamines with less likelihood of precursor reactive intermediates. Toxic species could then be formed by loss of H2O from the hydroxylamines.

Acetaminophen↗
PubMed1984

Structure-activity studies of beta-carboline analogs.

A number of beta-carboline analogs have been obtained or synthesized, and their in vitro receptor affinities and in vivo antagonist activities determined. The choice of analogs was made in order to explore the importance of the N9 -H, the aromatic nitrogen and the C3-ester moiety for high-receptor affinity and antagonist activity of this class of benzodiazepine antagonist. Among the analogs investigated, we describe the properties of 3-cyano-beta-carboline (1h), the first potent beta-carboline antagonist without a carbonyl at the C3-position. The results obtained indicate: (1) Specific interactions of the C3-substituent with key cationic receptor sites rather than electron-withdrawing properties are important for high-receptor affinity and antagonist activity. (2) Specific in-plane interactions of the aromatic nitrogen with a cationic receptor site, rather than stacking with neutral aromatic residues of the receptor are also important for high affinity and antagonist activity. (3) While the presence of an N9 -H enhances receptor affinity, interaction with an anionic receptor site does not appear essential for antagonist activity.

Animals↗
PubMed1984

Theoretical investigation of the role of clay edges in prebiotic peptide bond formation. I. Structures of acetic acid, glycine, H2SO4, H3PO4, Si(OH)4, Al(OH)4-.

Activation of amino acids appears to have played a crucial role in prebiotic peptide bond formation. As a model of this process in living systems, phosphates have been used as amino acid activators. The possible role of clay and other minerals has also been investigated. We are presently using ab initio methods to investigate the activation of amino acids by these agents, as an initial step in peptide bond formation. A model of this activation process is described by the reaction: ZCH2COOH + XO4Hn+1 --> ZCH2COOXO3Hn + H2O. The first step in such an investigation, reported here, was to determine the lowest energy structures of a suitable set of reactions. As initial models of amino acids, Z was chosen to be H and NH2, corresponding to acetic acid and glycine, respectively, XO4Hn+1 = H3PO4 represents a phosphate group, while Si(OH)4 describes an edge tetrahedral site of a clay mineral. Al(OH)4- was also included to represent tetrahedral edge site where the silicon is replaced by an aluminum. Finally, to complete the series XO4Hn+1, H2SO4 was added to the set of reactants. All species were optimized using the STO-3G and STO-3G* basis sets. For H3PO4 and Al(OH)4-, STO-3G* full optimizations were not possible. In these cases, certain torsional angles were optimized separately, then held at the optimized value, while the rest of the bond lengths and angles were optimized. All structures were compared to other calculations and to experimental geometries when available.

Acetic Acid↗
PubMed1984

Quantum chemical studies of a model for peptide bond formation. 3. Role of magnesium cation in formation of amide and water from ammonia and glycine.

The SN2 reaction between glycine and ammonia molecules with magnesium cation Mg2+ as a catalyst has been studied as a model reaction for Mg(2+)-catalyzed peptide bond formation using the ab initio Hartree-Fock molecular orbital method. As in previous studies of the uncatalyzed and amine-catalyzed reactions between glycine and ammonia, two reaction mechanisms have been examined, i.e., a two-step and a concerted reaction. The stationary points of each reaction including intermediate and transition states have been identified and free energies calculated for all geometry-optimized reaction species to determine the thermodynamics and kinetics of each reaction. Substantial decreases in free energies of activation were found for both reaction mechanisms in the Mg(2+)-catalyzed amide bond formation compared with those in the uncatalyzed and amine-catalyzed amide bond formation. The catalytic effect of the Mg2+ cation is to stabilize both the transition states and intermediate, and it is attributed to the neutralization of the developing negative charge on the electrophile and formation of a conformationally flexible nonplanar five-membered chelate ring structure.

Amides↗
PubMed1984

Theoretical structure-activity studies of benzodiazepine analogues. Requirements for receptor affinity and activity.

Conformational and electronic properties of a series of 1,4-benzodiazepine analogues and their specific interaction with a model cationic receptor site have been calculated using both empirical energy and semiempirical molecular orbital methods. The aim of these studies was to identify molecular properties and modes of receptor interaction which are determinants of relative receptor affinities and pharmacological activities for these anxiolytics. Analogues with variations in key positions of the 7-membered (B) ring, at positions C7, C8, and C9 of the fused phenyl (A) ring, and at positions 2' and 4' of the phenyl (C) ring were examined. The results indicate that both active and inactive analogues have similar low-energy conformations, arguing against this property as a modulator of recognition at the receptor. However, calculated molecular electrostatic potentials together with explicit model receptor interactions allowed the deduction that interactions with three cationic receptor sites are required for high-affinity analogues. The specific cationic site interactions are postulated with electron-withdrawing groups at C7, the C2 = O1 group, and the imine nitrogen, N4. Moreover, interactions of N4 with a model cationic receptor site are enhanced by halogen substituents at C2', but only when the phenyl ring is rotated by 30 degrees toward a more planar conformer, corresponding to an induced conformational change. If this enhancement is important, a 2'-Cl substituent on more rigid analogues of the 1,4-benzodiazepines with increased co-planarity of the phenyl C-ring and the C1'--C5 = N4 plane should have an even greater differential effect on receptor affinity.

Animals↗
PubMed1984

Metabolism and relative carcinogenic potency of chloroethanes: a quantum chemical structure-activity study.

Using the all-valence electron, semiempirical molecular orbital method, MNDO, properties have been identified and calculated for eight chloroethanes which can serve as indicators of their extent of transformation to alcohols by cytochrome P450 and the subsequent formation of aldehydes by loss of HCl from these alcohols. The assumption was made that these aldehydes are the active carcinogens of the chloroethanes and that they act as electrophiles in adduct formation with DNA bases. Electrophilic properties of these putative ultimate carcinogens have been calculated which are indicators of the rank order of carcinogenic activity of the parent compounds in susceptible species. Particularly relevant in this respect are (a) the electron affinity of aldehydes as measured by the energy of their electron accepting (lowest energy virtual) orbital, and (b) the net charge on the C alpha carbon, adjacent to the carbonyl carbon, which can participate in electrophilic attack on nucleophilic sites of DNA bases. The molecular properties identified in this study as indicators of rank order or carcinogenic activity of the parent chloroethanes are consistent with the importance of cytochrome P450 in transforming halohydrocarbons to active carcinogens and of acylchlorides and chloroaldehydes as the active form. Their validity and usefulness can be further tested in screening unknown and more complex chlorohydrocarbons for carcinogenic activity.

Acetaldehyde↗
PubMed1983

Metabolism and relative carcinogenic potency of chloroethylenes: a quantum chemical structure-activity study.

Properties of six chloroethylenes which could serve as indicators of their relative metabolic behavior and carcinogenic activity have been calculated using Modified Neglect of Diatomic Overlap (MNDO), a semiempirical, all valence electron, molecular orbital method. Possible pathways of transformation of parent compounds to acylchlorides, chloroaldehydes and epoxides--their putative ultimate carcinogens--were considered, and heats of formation and relative stabilities of intermediates were calculated. Our results indicate that carbonyl compounds could be formed with and without the intermediacy of epoxides, suggesting the possibility of more than one pathway in activation of parent compounds. Electronic properties of carbonyl products and epoxide carbocations, putative ultimate carcinogens which could serve as indicators of their relative electrophilicities, were also calculated. The results obtained indicated that the relative extent of metabolism to carbonyl products, rather than their electrophilicity, is a determinant of the relative carcinogenic activity of the parent compound. Of the various thermodynamic criteria investigated, four were found to be indicators of both relative metabolic behavior and carcinogenic activity.

Animals↗
PubMed1983

Computer-assisted analysis of receptor-binding studies of [3H]-naloxone and [3H]-DADL: a reinterpretation of the Na+ effect.

Computer-assisted analysis of competitive binding studies of [3H]-naloxone, [3H]-DADL, morphine and meperidine in the presence and absence of 100 mM NaCl have been made. The results are most consistent with a 3-site model of opiate receptors and indicate that in the presence of Na+ naloxone changes from a mu-specific (81%) to a more kappa-specific (63%) ligand. The large IC50 shift in inhibition of [3H]-naloxone by three agonists, DADL, morphine and meperidine is found not to be due to a decrease in affinity at any receptor site but rather to a low affinity of these agonists at "kappa" in the presence of Na+.

Animals↗
PubMed1982

Oxidation of carbon tetrachloride, bromotrichloromethane, and carbon tetrabromide by rat liver microsomes to electrophilic halogens.

In order to determine whether CCl4, CBrCl3, CBr4 or CHCl3 undergo oxidative metabolism to electrophilic halogens by liver microsomes, they were incubated with liver microsomes from phenobarbital pretreated rats in the presence of NADPH and 2,6-dimethylphenol. The analysis of the reaction mixtures by capillary gas chromatography mass spectrometry revealed that 4-chloro-2,6-dimethylphenol was a metabolite of CCl4 and CBrCl3 whereas 4-bromo-2,6-dimethylphenol was a metabolite of CBr4. The formation of the metabolites was significantly decreased when the reactions were conducted with heat denatured microsomes, in the absence of NADPH or under an atmosphere of N2. These results indicate that the chlorines of CBrCl3 and CCl4 and the bromines of CBr4 are oxidatively metabolized by rat liver microsomes to electrophilic and potentially toxic metabolites.

Animals↗
PubMed1981

Quantum chemical calculations on the two-step mechanism of proflavin binding to DNA.

Quantum chemical calculations on the binding of proflavin to DNA lead to a model in which the outside binding to a phosphate group leads to an induced fit in the intercalation receptor site. The calculations suggest hydrogen bonding of the amine groups of the outside bound proflavin to the anionic oxygen of the backbone phosphate. The resulting partial neutralization facilitates the conformational transitions required for intercalation. The results are consistent with the observed preference of proflavin for dCpdG over dGpdC sequences and with the observed kinetics of the binding reaction.

Acridines↗