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Biomedical subjects

Aihua Xie

Publications and source records attributed to Aihua Xie.

9 recordsLinked to original sources
PubMed2006

Probing the physicochemical and structural requirements for glycogen synthase kinase-3alpha inhibition: 2D-QSAR for 3-anilino-4-phenylmaleimides.

Glycogen synthase kinase-3alpha (GSK-3alpha) was recently found to be an attractive target for the treatment of Alzheimer's disease due to its dual action in the formation of both amyloid plaques and neurofibrillary tangles. It is also a viable target for many other diseases, such as type 2 diabetes. Reported herein is a 2D-QSAR exploration of the physicochemical (hydrophobic, electronic, and steric) and structural requirements among 3-anilino-4-phenylmaleimides toward GSK-3alpha binding. Using Fujita-Ban and Hansch QSAR analysis, electronic and steric interactions at the 4-phenyl ring and hydrophobic interactions at the 3-anilino ring are shown to be crucial. Analysis of the 4-phenyl ring of these compounds using common aromatic substituent constants showed electron-withdrawing and bulky ortho substituents as imperative for GSK-3alpha inhibition.

Glycogen Synthase Kinase 3↗
PubMed2006

3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold.

With annual death tolls in the millions and emerging resistance to existing drugs, novel therapies are needed against malaria. Wiesner et al. recently developed a novel class of antimalarials derived from farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold. The compounds displayed a wide range of activity, including submicromolar, against the multi-drug resistant Plasmodium falciparum strain Dd2. In order to investigate quantitatively the local physicochemical properties involved in the interaction between drug and biotarget, we used the 3D-QSAR methods CoMFA and CoMSIA to study some of the series, including the screened lead compound 2,5-bis-acylaminobenzophenone, 28 cinnamic acid derivatives, 29 N-(3-benzoyl-4-tolylacetylaminophenyl)-3-(5-aryl-2-furyl)acrylic acid amides, and 34 N-(4-substituted-amino-3-benzoylphenyl)-[5-(4-nitrophenyl)-2-furyl]acrylic acid amides. We found that steric, electrostatic, and hydrophobic properties of substituent groups play key roles in the bioactivity of the series of compounds, while hydrogen bonding interactions show no obvious impact. We built several highly predictive 3D-QSAR models, including a CoMSIA one composed of steric, electrostatic, and hydrophobic fields, with r(2)=0.94, q(2)=0.63, and r(pred)(2)=0.63. The results provide insight for optimization of this class of antimalarials for better activity and may prove helpful for further lead optimization.

Animals↗
PubMed2005

Picosecond thermometer in the amide I band of myoglobin.

The amide I and II bands in myoglobin show a heterogeneous temperature dependence, with bands at 6.17 and 6.43 microm which are more intense at low temperatures. The amide I band temperature dependence is on the long wavelength edge of the band, while the short wavelength side has almost no temperature dependence. We compare concepts of anharmonic solid-state crystal physics and chemical physics for the origins of these bands. We suggest that the long wavelength side is composed of those amino acids which hydrogen bond to the hydration shell of the protein, and that temperature dependent bands can be used to determine the time it takes vibrational energy to flow into the hydration shell. We determine that vibrational energy flow to the hydration shell from the amide I takes approximately 20 ps to occur.

Amides↗
PubMed2005

A vibrational spectral maker for probing the hydrogen-bonding status of protonated Asp and Glu residues.

Hydrogen bonding is a fundamental element in protein structure and function. Breaking a single hydrogen bond may impair the stability of a protein. We report an infrared vibrational spectral marker for probing the hydrogen-bond number for buried, protonated Asp or Glu residues in proteins. Ab initio computational studies were performed on hydrogen-bonding interactions of a COOH group with a variety of side-chain model compounds of polar and charged amino acids in vacuum using density function theory. For hydrogen-bonding interactions with polar side-chain groups, our results show a strong correlation between the C=O stretching frequency and the hydrogen bond number of a COOH group: approximately 1759-1776 cm(-1) for zero, approximately 1733-1749 cm(-1) for one, and 1703-1710 cm(-1) for two hydrogen bonds. Experimental evidence for this correlation will be discussed. In addition, we show an approximate linear correlation between the C=O stretching frequency and the hydrogen-bond strength. We propose that a two-dimensional infrared spectroscopy, C=O stretching versus O-H stretching, may be employed to identify the specific type of hydrogen-bonding interaction. This vibrational spectral marker for hydrogen-bonding interaction is expected to enhance the power of time-resolved Fourier transform infrared spectroscopy for structural characterization of functionally important intermediates of proteins.

Aspartic Acid↗
PubMed2004

3D QSAR studies on peroxisome proliferator-activated receptor gamma agonists using CoMFA and CoMSIA.

The peroxisome proliferator-activated receptors (PPARs) have increasingly become attractive targets for developing novel anti-type 2 diabetic drugs. We employed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) to study three-dimensional quantitative structure-activity relationship (3D QSAR) based on existing agonists of PPARgamma (including five thiazolidinediones and 74 tyrosine-based compounds). Predictive 3D QSAR models with conventional r2 and cross-validated coefficient (q2) values up to 0.974 and 0.642 for CoMFA and 0.979 and 0.686 for COMSIA were established using the SYBYL package. These models were validated by a test set containing 18 compounds. The CoMFA and CoMSIA field distributions are in general agreement with the structural characteristics of the binding pockets of PPARgamma, which demonstrates that the 3D QSAR models built here are very useful in predicting activities of novel compounds for activating PPARgamma.

Computer Simulation↗
PubMed2004

Quantitative structure-activity relationship study of histone deacetylase inhibitors.

Histone deacetylases (HDACs) play a critical role in gene transcription and have become a novel target for the discovery of drugs against cancer and other diseases. During the past several years there have been extensive efforts in the identification and optimization of histone deacetylase inhibitors (HDACIs) as novel anticancer drugs. Here we report a comprehensive quantitative structure-activity relationship (QSAR) study of HDACIs in the hope of identifying the structural determinants for anticancer activity. We have identified, collected, and verified the structural and biological activity data for 124 compounds from various literature sources and performed an extensive QSAR study on this comprehensive data set by using various QSAR and classification methods. A highly predictive QSAR model with R(2) of 0.76 and leave-one-out cross-validated R(2) of 0.73 was obtained. The overall rate of cross-validated correct prediction of the classification model is around 92%. The QSAR and classification models provided direct guidance to our internal programs of identifying and optimizing HDAC inhibitors. Limitations of the models were also discussed.

Animals↗
PubMed2001

Excited-state lifetimes of far-infrared collective modes in proteins.

Vibrational excitations of low frequency collective modes are essential for functionally important conformational transitions in proteins. Here we report the first direct measurement on the lifetime of vibrational excitations of the collective modes at 87 microm (115 cm(-1)) in bacteriorhodopsin, a transmembrane protein. The data show that these modes have extremely long lifetime of vibrational excitations, over 500 ps, accommodating 1500 vibrations. We suggest that there is a connection between this relatively slow anharmonic relaxation rate of approximately 10(9) sec(-1) and the similar observed rate of conformational transitions in proteins, which require multilevel vibrational excitations.

Protein Conformation↗
PubMedDate not supplied

Eigenvalue analysis of peroxisome proliferator-activated receptor gamma agonists.

Eigenvalue analysis (EVA) was conducted on a series of potent agonists of peroxisome proliferator-activated receptor gamma (PPARgamma). Predictive EVA quantitative structure-activity relationship (QSAR) models were established using the SYBYL package, which had conventional r2 and cross-validated coefficient (q2) values up to 0.920 and 0.587 for the AM1 method and 0.863 and 0.586 for the PM3 method, respectively. These models were validated by a test set containing 18 compounds. The capability to predict by these two models for PPARgamma agonists, with the best predictive r2pred value of 0.614 for AM1 and 0.822 for PM3 methods, set a successful example for applying a similar approach in building QSAR models for PPARalpha and -delta that could potentially offer a new opportunity in the design of novel PPAR modulators.

Models, Chemical↗