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  • 1
    Electronic Resource
    Electronic Resource
    Structural and electronic requirements for binding at the Mu-opioid receptor (1992)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 44 (1992), S. 235-250 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A pharmacophore for μ-opioid receptor recognition based on a study of the fentanyl class of opioids has recently been characterized in our laboratories. To validate this pharmacophore, we have extended our theoretical studies to include four opiate analogs from structurally different classes and with high affinity but varying selectivity for the μ-opiate receptor. An extensive conformational search of the flexible regions of these compounds has been carried out at two levels of approximations, using the CHARMm force field and the semiempirical molecular orbital method AM1. In a subsequent step, we have determined a series of structural, environmental, and electronic properties for each low-energy conformer of the analogs studied. All four analogs studied can assume a low-energy conformation in which at least three of the four stereoelectronic properties identified as modulators of recognition in the fentanyls are present in the same spatial arrangement. These results provide additional evidence for the plausibility of the proposed pharmacophore for μ-opioid receptor recognition. © 1992 John Wiley & Sons, Inc.
    Additional Material: 8 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560440211
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  • 2
    Electronic Resource
    Electronic Resource
    Conformational study of Met-enkephalin in its zwitterionic form (1992)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 44 (1992), S. 263-275 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: An extensive exploration of Met-enkephalin in its zwitterionic form has been carried out, in order to characterize the different low-energy conformational domains accessible to this pentapeptide. The study builds on previous studies carried out in our lab for the neutral molecule, which provided the initial geometries from which the conformational space of the charged molecule could be scanned. The initial conformations were subjected to a series of high- and lowtemperature molecular dynamics simulations. Snapshots along each trajectory were taken, minimized, and used as starting points in further MD trajectories until no lower-energy conformers could be characterized. The CHARMm force field was used throughout the study for this purpose. The same search strategy was used in these studies simulating two different environmental conditions, a distance-dependent dielectric ∊ = r and a high constant dielectric ∊ = 80. In the low dielectric environment, the formation of the salt bridge dominates the structure. In the high dielectric environment, the screening of the electrostatic interactions results in weaker intramolecular interactions. In both cases, the Gly2-Gly3 β-turn-type structures are preferred over the Gly3-Phe4 turns, in marked contrast to what is found for the neutral molecule. The lowest-energy structures from both environmental conditions were reoptimized in the presence of a cluster of explicit water molecules. Reoptimization of the structures considering explicit water structures did not result in significant conformational changes for the structures characterized with the ε = r or ε = 80 environments.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560440213
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  • 3
    Electronic Resource
    Electronic Resource
    Theoretical studies of the oxidation of N- and S-containing compounds by cytochrome P450 (1993)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 48 (1993), S. 815-826 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Many xenobiotics containing N or S heteroatoms are metabolized by the cytochrome P450s, leading to a variety of products which can be toxic, carcinogenic, or detoxifying. Thus, it is important to try to establish molecular criteria that modulate competitive product formation for these types of compounds. In the absence of 3D structures for the P450 isozymes that are responsible for the oxidations of N- and S-containing compounds, we have focused here on the characterization and identification of possible electronic and thermodynamic factors that could be modulators of different types of product formation. Specifically, the competition among N-oxidation, N-hydroxylation and Cα-hydroxylation for three amines were examined. Similarly, three thioethers were studied for their internal competition between S-oxidation and Cα-hydroxylation. The results obtained indicate that the stability of the cation radical intermediate formed by the one electron transfer mechanism is not a determinant of differences in product distribution between the two types of compounds. Rather, relative product stability appears to be a significant modulator of product distribution explaining why S-oxide formation is favored over N-oxide and why Cα-hydroxylation is usually favored over N-oxide formation in amines. © 1993 John Wiley & Sons, Inc.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560480873
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  • 4
    Electronic Resource
    Electronic Resource
    Binding of flexible ligands to proteins: Valproic acid and its interaction with cytochrome P450cam (1993)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 48 (1993), S. 161-180 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A combined theoretical and experimental study of the binding and interaction of valproic acid (VPA) with the bacterial cytochrome P450cam enzyme and the determination of regio- and stereoselective hydroxylation product distribution was performed. From the experiments, C4—;OH VPA was found to be the predominant hydroxylation product with a small amount of C5—OH VPA formed. The experimental stereoselectivity of hydroxylation was 2R4S 〉 ∼ 2S4R 〉 2R4R 〉 ∼ 2S4S and 2S5 〉 ∼ 2R5. The overall goals of the theoretical study were twofold: (1) to characterize as completely as possible, using energy optimization and molecular dynamics simulations, the interactions of flexible ligands with their target proteins, and (2) to determine the extent to which these results could be used to develop criteria to predict or explain the experimentally observed regio- and stereoselectivity of hydroxylation of the flexible ligands. Among the useful insights into the behavior of flexible ligands upon binding to their traget proteins obtained are (1) a large change in conformation occurs for many conformers of VPA upon binding to P450cam, (2) low- energy conformers of VPA do not necessarily lead to optimum interactions with the target protein, and (3) the most favorable mode of interaction of this flexible ligand with the protein binding site has been identified and found to be a result of strong electrostatic interactions between VPA and both Tyr96 and Asp297. For the study of the hydroxylated VPA products, the challenging aspect of this problem was to determine criteria for weighing the contribution of each of the possible protein-ligand complexes. To this end, various possibilities were examined and compared with the experimental results. No single complex was found to reproduce the observed experimental regio- and stereoselectivity. This result indicates that more than one bioactive form of VPA contributes to its oxidation. Results most consistent with experiment are obtained by using the interaction energy of the protein-ligand complex as a criterion for including its contribution to product formation. Although there are remaining disparities between predicted and observed product distributions, the combined theoretical and experimental effort has led to insights into the modes of interaction of this flexible ligand that lead to its observed product specificity. © 1993 John Wiley & Sons, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560480718
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  • 5
    Electronic Resource
    Electronic Resource
    Steric and electronic criteria for teratogenicity of short chain aliphatic acids (1990)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 38 (1990), S. 173-187 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Esters of short chain aliphatic acids are commonly used in industry as solvents which are easily metabolized to their acid analogs. Some of these aliphatic acids are also by-products of industrial products, e.g., 2-ethyl hexanoic acid is a metabolite of the plasticizer diethylhexyl phthalate and methoxy acetic acid is the principal metabolite of the glyco ether, 2-methyl ethanol. Many of these aliphatic acids exhibit a variety of toxic effects. Cytochrome P450 is involved in the metabolism of aliphatic acids resulting in liver toxicity by formation of a toxic metabolite. These acids also act as sedatives, possibly by occupying a hydrophobic site in the brain. Certain aliphatic acids have been shown to cause teratogenic effects in laboratory animals for which the mechanism is as yet unknown. The techniques of computational chemistry can be useful in helping to formulate such mechanisms and ultimately for computer-aided risk assessment of potentially toxic compounds. The current study focuses on developing reliable molecular indicators of the teratogenic behavior of selected aliphatic acids, by investigating the role of conformational, physical, and electronic properties. The geometries of the aliphatic acids used for analysis were optimized using CHARMm and AM1. Our results show that pKa and log P do not seem to be reliable modulators of teratogenic potency. By contrast, the conformation of the acid analogs, especially near the acid group, appears to be important for activity. These results implicate a possible mechanism of action involving a conformationally specific binding site or carrier protein.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560381718
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  • 6
    Electronic Resource
    Electronic Resource
    Properties of selective type I benzodiazepine receptor ligands (1991)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 40 (1991), S. 131-149 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Conformational studies on zolpidem, 2-oxoquazepam, and ICI 190,622, three type I selective benzodiazepine receptor ligands, are presented. The semiempirical quantum mechanical AM1 technique was used, and all possible torsions were rotated systematically in 30° increments. In addition, each of the structures was subjected to molecular dynamics simulation at 310 K, to study their conformational flexibility at physiologically relevant temperatures. Zolpidem and 2-oxoquazepam have two low-energy conformers each that can not interconvert. By contrast, ICI 190,622 has several low-energy equilibrium structures, each of which could be accessed from any other minimum in the simulation. For each of these three selective analogs, for CL 218,872, and for the nonselective diazepam, flunitrazepam, and triazolam, steric and electronic properties were calculated and examined for their role as determinants of type 1 receptor recognition and selectivity. Specifically, the “sterimol” parameters, which provide quantitative measures of the shape, and heats of protonation for each analog were calculated. The geometric parameter that describes the maximum separation between any two points on the molecular surface appears to be good discriminant of selectivity.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560400716
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  • 7
    Electronic Resource
    Electronic Resource
    Comparison of computational models for simulating heme proteins: A study of cytochrome C peroxidase (1992)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 44 (1992), S. 87-107 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: We have investigated four computational models of the resting state and HOOH-bound complex of a heme protein, cytochrome c peroxidase (CCP), to determine the most efficient methodology that yields reliable results. Previous studies have focused on the overall dynamic structure of proteins and not explicitly on the motion of small molecules and their effect on nearby residues. In this study, the effects of dielectric, boundary constraints, explicit inclusion of solvent, and charges on the heme unit have specifically been examined. For the case studied here, in which interactions with water are very important, it was found that, contrary to commonly accepted procedures, a distance-dependent dielectric (ε = 4R) with a constrained protein and no solvent resulted in unacceptably large deviations from more accurate models. In this case, even a buried Trp residue hydrogen bonded to the water network showed large deviations due to the exaggerated motions of the waters. However, use of a constant dielectric (ε = 1) with the same constraints resulted in a computationally efficient model that yielded properties very similar to the more accurate models. © 1992 John Wiley & Sons, Inc.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560440712
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  • 8
    Electronic Resource
    Electronic Resource
    Conformational and electronic properties of met-enkephalin (1991)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 40 (1991), S. 165-181 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The results of a previous extensive exploration of the conformational space of met-enkephalin embedding the peptide in a distance dependent dielectric and in continuum dielectrics of constants 10 and 80, are used in an attempt to obtain information regarding the most adequate environmental conditions for the characterization of the bioactive structures of these peptides. To this end, we used experimental information as well as overlaps with PET, a potent opiate narcotic, to select the most promising candidate structures among those obtained in the different environments. A dielectric constant of 80 provides the only two conformations that fulfill all the characteristics inferred for the bioactive form. In a parallel effort, we have begun to examine electronic properties of met-enkephalin peptides and their dependence on conformation by computing them for nine low energy conformations after reoptimization using the AM1 semiempirical quantum mechanical method.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560400718
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  • 9
    Electronic Resource
    Electronic Resource
    Introduction (1992)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 44 (1992), S. 95-96 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560440202
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  • 10
    Electronic Resource
    Electronic Resource
    Role of axial ligand in the electronic structure of model compound I complexes (1992)
    New York, NY : Wiley-Blackwell
    International Journal of Quantum Chemistry 44 (1992), S. 251-261 
    Details
    ISSN: 0020-7608
    Keywords: Computational Chemistry and Molecular Modeling ; Atomic, Molecular and Optical Physics
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A quantum chemical study of the two low-lying quartet states of seven model compound I iron-porphyrin complexes with varying axial ligands has been carried out using the INDO method. The varying axial ligands included in this study are five that are models for those in the intact enzymes: imidazole and imidazolate (model peroxidase HRP and CCP), CH3CONH2 (Gln175 mutant of CCP), PhO-1 (catalase), CH3S-1 (P450), and two that have been used in biomimetics of these enzymes: Cl-1 (hemin) and PhS-1 (model P450s). The purpose of these studies was to determine the role of the axial ligands in determining (i) the relative energies of the two nearly degenerate quartet electronic states of compound I, involved either as an a1u or a2u porphyrin π cation radical and (ii) the electron and spin distributions in the a1u and a2u radical cations of compound I. For most of the model complexes, including both HRP-I and CAT-I, a moderate effect of the axial ligand on the relative energy of these two states was observed and the a1u radical cation was found to be the ground state. The energy order of these two radical cations, however, was reversed in the P450-I model complexes, indicating an association of the unique property of the Fe=O bond breaking with an a2u radical cation. The symmetry-allowed overlap between the Fe=O and 3a2u orbitals may lower the activation energy for the Fe=O bond cleavage in P450-I. However, the calculated electronic and spin properties, including the unpaired spin and net charge on the oxygen and the Fe=O bond overlap density, important determinants of the reactivity of this complex in the ligand-Fe=O region, are very similar for all complexes and in both cation states. © 1992 John Wiley & Sons, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/qua.560440212
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