Prediction of proton magnetic resonance shifts: The dependence on hydrogen charges obtained by iterative partial equalization of orbital electronegativity

Gasteiger, Johann; Marsili, Mario

doi:10.1002/mrc.1270150408

Cited by 131 publications

(55 citation statements)

References 26 publications

(3 reference statements)

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“…Calculations of the Atomic Charges. Five different kinds of partial atomic charges were considered: (1) Gasteiger-Marsili charges, [36][37][38] (2) Gasteiger-Hückel charge, 39 (3) MMFF94 charges, 35 (4) the electrostatic potential fit charges at the AM1 level (ESP-AM1), 40 and (5) the Mulliken population analysis atomic charges at the AM1 level (MPA-AM1). 40 Both of the Gasteiger-Marsili and the Gasteiger-Hückel methods calculate atomic charges based on information about the atoms and their connectivity within the molecule.…”

Section: Methodsmentioning

confidence: 99%

Mapping the Binding Site of a Large Set of Quinazoline Type EGF‐R Inhibitors Using Molecular Field Analyses and Molecular Docking Studies.

et al. 2003

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In the current work, three-dimensional QSAR studies for one large set of quinazoline type epidermal growth factor receptor (EGF-R) inhibitors were conducted using two types of molecular field analysis techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). These compounds belonging to six different structural classes were randomly divided into a training set of 122 compounds and a test set of 13 compounds. The statistical results showed that the 3D-QSAR models derived from CoMFA were superior to those generated from CoMSIA. The most optimal CoMFA model after region focusing bears significant cross-validated r 2 cv of 0.60 and conventional r 2 of 0.92. The predictive power of the best CoMFA model was further validated by the accurate estimation to these compounds in the external test set, and the mean agreement of experimental and predicted log(IC 50 ) values of the inhibitors is 0.6 log unit. Separate CoMFA models were conducted to evaluate the influence of different partial charges (Gasteiger-Marsili, Gasteiger-Hückel, MMFF94, ESP-AM1, and MPA-AM1) on the statistical quality of the models. The resulting CoMFA field map provides information on the geometry of the binding site cavity and the relative weights of various properties in different site pockets for each of the substrates considered. Moreover, in the current work, we applied MD simulations combined with MM/ PBSA (Molecular mechanics/Possion-Boltzmann Surface Area) to determine the correct binding mode of the best inhibitor for which no ligand-protein crystal structure was present. To proceed, we define the following procedure: three hundred picosecond molecular dynamics simulations were first performed for the four binding modes suggested by DOCK 4.0 and manual docking, and then MM/PBSA was carried out for the collected snapshots. The most favorable binding mode identified by MM/PBSA has a binding free energy about 10 kcal/mol more favorable than the second best one. The most favorable binding mode identified by MM/PBSA can give satisfactory explanation of the SAR data of the studied molecules and is in good agreement with the contour maps of CoMFA. The most favorable binding mode suggests that with the quinazoline-based inhibitor, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 766, not Thr 830 as proposed by Wissner et al. (J. Med. Chem. 2000, 43, 3244). The predicted complex structure of quinazoline type inhibitor with EGF-R as well as the pharmacophore mapping from CoMFA can interpret the structure activities of the inhibitors well and afford us important information for structure-based drug design.

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Section: Methodsmentioning

confidence: 99%

Mapping the Binding Site of a Large Set of Quinazoline Type EGF‐R Inhibitors Using Molecular Field Analyses and Molecular Docking Studies.

et al. 2003

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“…redhat.com). Atomic charges were calculated by the method of Gasteiger and Marsili (1981). Energy minimizations were performed using Tripos force field with the default force field settings and charges with distance-dependent dielectric and conjugate gradient method with a convergence criterion of 0.01 kcal mol Ϫ1 (Clark et al, 1989).…”

Section: The Role Of T-cells In Drug Hypersensitivitymentioning

confidence: 99%

Characterization of the T-Cell Response in a Patient with Phenindione Hypersensitivity

Naisbitt¹,

Farrell²,

Chamberlain³

et al. 2005

J Pharmacol Exp Ther

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The oral anticoagulant phenindione [2-phenyl-1H-indene-1,3(2H)-dione] is associated with hypersensitivity reactions in 1.5 to 3% of patients, the pathogenesis of which is unclear. We describe a patient who developed a severe hypersensitivity reaction that involved both the skin and lungs. A lymphocyte transformation test showed proliferation of T-cells from the hypersensitive patient, but not from four controls on exposure to phenindione in vitro. Drug-specific T-cell clones were generated and characterized in terms of their phenotype, functionality, and mechanism of antigen presentation. Forty-three human leukocyte antigen class II restricted CD4ϩ ␣␤ T-cell clones were identified. T-cell activation resulted in the secretion of interferon-␥ and interleukin-5. Five of seven clones proliferated with phenindione alone, whereas two clones also proliferated with 2-phenylindene. Certain T-cell clones were also stimulated by R-and S-warfarin; computer modeling revealed that warfarin can adopt a phenindione-like structure. Phenindione was presented to T-cells via two pathways: first, bound directly to major histocompatibility complex and second, bound to a processed peptide. Our data show that CD4 ϩ T-cells are involved in the pathophysiology of phenindione hypersensitivity. There may be cross-sensitivity with warfarin in some phenindione hypersensitive patients.

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“…5,5,5-Triphenylpentyl-1-sulfate (24) was synthesized starting from 5,5,5-triphenyl-1-pentanol and pyridine sulfur trioxide according to Duff (14). For the synthesis of 5Ј,5Ј,5Ј-triphenylpentyl-2-malonic acid (25), triphenylmethyl lithium was the starting material according to Gilman and Gaj (15). The triphenylmethyl lithium was condensed on 1-bromo-4-chlorobutane, and chloride compound obtained was substituted by iodine in order to increase its reactivity toward malonate anion.…”

Section: Synthesis Of Inhibitorsmentioning

confidence: 99%

Mechanism of inhibition of rat liver bilirubin UDP-glucuronosyltransferase by triphenylalkyl derivatives

Said

Battaglia

Elass

et al. 1998

J. Biochem. Mol. Toxicol.

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Prediction of proton magnetic resonance shifts: The dependence on hydrogen charges obtained by iterative partial equalization of orbital electronegativity

Cited by 131 publications

References 26 publications

Mapping the Binding Site of a Large Set of Quinazoline Type EGF‐R Inhibitors Using Molecular Field Analyses and Molecular Docking Studies.

Mapping the Binding Site of a Large Set of Quinazoline Type EGF‐R Inhibitors Using Molecular Field Analyses and Molecular Docking Studies.

Characterization of the T-Cell Response in a Patient with Phenindione Hypersensitivity

Mechanism of inhibition of rat liver bilirubin UDP-glucuronosyltransferase by triphenylalkyl derivatives

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