Biomedical subjects

Jianwei Zou

Publications and source records attributed to Jianwei Zou.

5 recordsLinked to original sources

PubMed2006

3D QSAR for GSK-3beta inhibition by indirubin analogues.

Glycogen synthase kinase 3 (GSK-3) plays an important role in a diverse number of regulatory pathways by phosphorylation of several different cellular targets and its inhibitors have been evaluated as promising drug candidates. Indirubin analogues show favorable inhibitory activity targeting GSK-3beta, which is closely related to the property and position of substituents. Two methods were used to build 3D-QSAR models for indirubin derivatives. The conventional 3D-QSAR (ligand-based) studies were performed based on the lower energy conformations employing atom fit alignment rule. The receptor-based 3D-QSAR models were also derived using bioactive conformations obtained by docking the compounds to the active site of GSK-3. Conclusions of models based on two methods are similar and reliable. The results indicate that both ligand-based and receptor-based are feasible tools to build 3D-QSAR models. Contour maps of the receptor-based CoMSIA model (q(2) = 0.766, r(2) = 0.908, N (number of components) = 5) including the steric, electronic and hydrophobic fields were taken as representative to explain factors affecting activities of inhibitors.

Antibiotics, Antineoplastic↗

PubMed2005

Triangular halogen trimers. A DFT study of the structure, cooperativity, and vibrational properties.

Triangular halogen trimers (RX)3, where X = Br, I and R represents H, H3C, H2FC, HF2C, F3C, CH2=CH, CH[triple bond]C, and Ph, have been investigated using the density functional theory in the Perdew, Burke, and Ernzerhof method. We report herein the optimized geometries of the stable structures, their vibrational frequencies, and binding energies with the two- and three-body terms. All trimer structures possess a cyclic array of halogen atoms in the type II approach by virtue of the nonspherical atomic charge distribution around the halogens. The Br...Br interactions in trimers are very weak, whereas the I...I interactions in trimers are relatively stronger. While all bromine trimers and most of iodine trimers are predicted to be noncooperative, three of iodine trimers show weak cooperativity. The analysis of vibration modes reveals that all halogen trimers exhibit no especially remarkable frequency shifts. It is also shown that the electrostatic contribution plays a major role in the halogen...halogen interactions in halogen trimers. In contrast to bromine trimers, the relative contribution of charge-transfer component to the halogen...halogen interactions becomes more important for iodine trimers.

Journal Article↗

PubMed2005

Some insights into the stereochemistry of inhibition of macrophage migration inhibitory factor with 2-fluoro-p-hydroxycinnamate and its analogues from molecular dynamics simulations.

Macrophage migration inhibitory factor (MIF) exhibits tautomerase activity on phenylpyruvate and has E-stereochemistry preference. To investigate the binding modes of its competitive inhibitors and evaluate their binding affinities, molecular dynamics simulations together with MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) analysis were performed on MIF complexed with (E)-2-fluoro-p-hydroxycinnamate and five analogues. Pro-1 was discovered to form a bifurcated hydrogen bond between its protonated nitrogen and carboxylate oxygens of E-ligands and Tyr-36. No hydrogen bonds were found between Pro-1 and Z-ligands. This distinct binding characteristic of E- and Z-ligands with Pro-1 may be the main factor for the large difference in their binding affinities, which is consistent with the previous report that Pro-1 is essential for the catalytic activity of MIF. MM-PBSA analysis revealed that energy components including van der Waals, electrostatic, and hydrophobic interactions are in favor of binding, among which electrostatic interactions are predominant to the binding affinity difference.

Cinnamates↗

PubMed2005

Study of a ligand complexed with Cdk2/Cdk4 by computer simulation.

Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745-749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K(i) = 6 nM) but a low affinity with cyclin-dependent kinase 4 (K(i) = 1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy calculations to analyze the interactions. A rational 3D model of the Cdk4-NU6102 complex is built. Asp86 is a key residue that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4.

Amino Acid Sequence↗

PubMed2002

3D-QSAR studies on 4-hydroxyphenylpyruvate dioxygenase inhibitors by comparative molecular field analysis (CoMFA).

A comparative molecular field analysis (CoMFA) of alkanoic acid 3-oxo-cyclohex-1-enyl ester and 2-acylcyclohexane-1,3-dione derivatives of 4-hydroxyphenylpyruvate dioxygenase inhibitors has been performed to determine the factors required for the activity of these compounds. The substrate's conformation abstracted from dynamic modeling of the enzyme-substrate complex was used to build the initial structures of the inhibitors. Satisfactory results were obtained after an all-space searching procedure, performing a leave-one out (LOO) cross-validation study with cross-validation q(2) and conventional r(2) values of 0.779 and 0.989, respectively. The results provide the tools for predicting the affinity of related compounds, and for guiding the design and synthesis of new HPPD ligands with predetermined affinities.

4-Hydroxyphenylpyruvate Dioxygenase↗