Showing papers by "Kaixian Chen published in 2000"

Building three-dimensional structures of HIV-1 coreceptor CCR5 and its interaction with antagonist TAK779 by comparative molecular modeling.

Abstract: "AIM: To study the mechanism of interaction of CCR5 receptor with its antagonist TAK779. METHODS: Comparative molecular modeling has been used to develop the 3D-structural models of CCR5 receptor and its complex with TAK779. Molecular mechanics has been applied to optimize the above molecular models. Quantum mechanics has been utilized to calculate the structural information of TAK779. DOCK4.0 program is employed to dock the TAK779 molecular into the binding site of CCR5 receptor. RESULTS: The 3D-structural model of CCR5 receptor is constructed using the 3D-model of frog rhodopsin as a template. The binding pocket is situated in the transmembrane helices 3, 5, 6, and 7, and it is composed of conserved residues of Tyr108, Gly111, Ser114, Glu283, Gly286, and Cys290, and conservatively varied residues including Thr105, Leu107, Phe112, Gly115, Lys197, and Met287. O1, N7, N17, and O19 of TAK779 are the active center of TAK779. The pyran cycle and the aminium group of TAK779 interact with residues in the binding pocket of CCR5 receptor, the other part of TAK779 interacts with residues from the extracellular loops of CCR5. The binding energy of TAK779 with CCR5 is -51.606 kcal/mol. CONCLUSION: The model constructed and the interaction mode reported in the present study are useful in further understanding the molecular mechanism of receptor-virus recognition and designing new inhibitors of HIV-1 infection."

A density functional theory (DFT) calculation of the geometry and vibrational spectrum of natural product, ginkgolide B

Abstract: A quantum chemistry calculation at DFT-B3LYP/6-31G ∗ level on the geometry and IR spectrum of ginkgolide B was performed. The fully optimised geometry of ginkgolide B was found to be consistent with X-ray crystal structure. In addition, some important thermodynamic parameters were provided. The predicted vibrational bands of ginkgolide B scaled by a scaling factor of 0.945 were perfectly aligned to the experimental IR spectrum. Normal mode analysis on all 156 predicted bands showed that the stretching of O–H bonds of alcohol hydroxyl groups correspond to modes 156, 155 and 154 (from 3501 to 3443 cm −1 ). The stretching of C O bonds of carbonyl groups result in modes 132, 131 and 130 (from 1788 to 1764 cm −1 ). These assigned results were in accordance with what had been assigned in experiment based on IR spectroscopy. However, our normal mode analyses on the bands below 1192 cm −1 (mode 97) showed that none of these bands could be simply assigned to the stretching of a C–O bond. These bands are the results of coupling between the breathing of condensed ring structure and some other vibrations, such as the stretching of C–O bond or the rocking of C–H bond. Some of the bands that had been assigned to the stretching of C–O bond in experiment could be partly contributed by the vibration of C–O bonds. Furthermore, this study result showed that the stretching of C–H bond, and the rocking of t -Bu, methyl and methenyl groups can be located at the bands around 2900 and 1460 cm −1 , respectively.

Building 3D-structural model of kappa opioid receptor and studying its interaction mechanism with dynorphin A(1-8).

Abstract: "AIM: To construct the 3D-structural model of human kappa opioid receptor (HKOR) and study its interacting mechanism with dynorphin A(1-8) (Dyn8). METHODS: Comparative molecular modeling was applied to build the 7 transmembrane (TM) helical domain of HKOR using the bovine rhodopsin (OPSD) model as a template. Molecular dynamics was performed to minimize the HKOR model and to simulate the 3D-structure of Dyn8 based on the NMR results of dynorphin A(1-14). The extracellular loops (EL) were built by self-constructed database searching. DOCK4.0 program was performed to construct Dyn8 complex with HKOR. RESULTS: (1) The model of HKOR was obtained and validated by theoretical and experimental data. (2) The Dyn8-HKOR interacting mechanism is reasonably explained: Side chain of residue Asp138 interacts with protonated nitrogen atom at the N-terminal residues of Dyn8 through electrostatic and hydrogen bonding, which play an important role in ligand binding with receptor. (3) Negatively charged amino acids in the second extracellular loop (EL2) as Asp223 and Glu209 interact with the C-terminal positively charged residues in Dyn8, and Glu209 is a likely determinant of peptide ligand specificity. CONCLUSION: Some amino acid residues positioned in EL2, TM3, TM4, and TM5 form the binding site and therefore determine the selectivity of kappa peptide agonist."

Study on mechanism of interaction of nociceptin and opioids binding with opioid receptor-like 1 receptor.

Abstract: "AIM: To study the mechanism of interaction of nociceptin and opioids with ORL1 receptor. METHODS: Molecular dynamics study was carried out before nociceptin was manually docked into the binding site of ORL1 receptor; DOCK4.0 program was applied to dock four stereoisomers of lofentanyl and etorphine into the binding pocket of ORL1 receptor; Binding energies were calculated, the relationship between binding energy and binding affinity was studied. RESULTS: Nociceptin fits well into the binding pocket, the N-terminal FGGF tetrapeptide is located in the inner region of the binding cavity, the nociceptin (5-7) interacts with the conservatively variable residues near the other end of binding pocket, and maybe determines selectivity of ORL1 receptor over dynorphin A, the positively charged core of nociceptin (8-13) binds predominantly with negatively charged EL-2 loop, which is thought to be able to mediate receptor activation. The shortest fully active analogue of nociceptin (1-13) is also discussed. The main difference between these two opioids and nociceptin exists in the kinds and the number of conserved and variable residues in the binding pocket and thereafter in the strength of their interaction. Prediction for binding affinities of four stereoisomers of lofentanyl has been performed based on their binding energies, the similar pharmacophore of lofentanyl and other fentanyl analogs, and the good correlation between binding energies and their experimental binding affinities (-log Ki values). CONCLUSION: Ligand docking results from this study are helpful in clarifying experimental observations of ligands interaction with opioid receptors, thus furthering biological investigations."

Molecular modeling on solvent effect and interaction mechanism of fentanyl analogs to mu-opioid receptor.

Abstract: AIM: To do theoretical study about solvation effect and interaction mechanism of fentanyl analogs (FA) to mu opioid receptor (microOR). METHODS: Flexible docking (FlexiDock) was performed by using the possible active conformations of FA and optimized 3D structure of mu opioid receptor. Binding energies were calculated. Comparative molecular force field analysis (CoMFA) and quantitative structure activity relationship (QSAR) studies were carried out based on results of flexible docking. Solvation effects were considered by studying interaction of FA with water molecules. Partial least square (PLS) analysis was used to calculate regression equation for analgesic activities using binding energies as descriptive factor. RESULTS: 1) Binding conformations of these analogs derived by flexible docking were reasonable. 2) It was most possible for the FA to exist in water solution in the form of binding conformations. 3) Energetic calculation and QSAR analysis showed a good correlation between the calculated binding energies of FA and their analgesic activities. 4) Based on the 3D-model, the possible interaction mechanism of FA with mu opioid receptor can be illustrated reasonably. CONCLUSION: The nature of the correlation between the binding affinities and analgesic activities of FA was explained by our modeling result.

Comparative molecular modeling on 3D-structure of opioid receptor-like 1 receptor.

Abstract: "AIM: To build the three-dimensional structure of opioid receptor-like 1 (ORL1) receptor. METHODS: Structural elements of ORL1 receptor were predicted from sequence alignments of opioid and related receptors of G protein-coupled receptor (GPCR) based on (i) the consensus, biophysical interpretations of alignment-derived properties, and (ii) tertiary structural homology to frog rhodopsin; The extracellular loops of ORL1 were built by self-constructed database searching based on geometrical constraints; initial model was refined computationally with energy minimization by molecular mechanics method. RESULTS: The calculated structure of ORL1 receptor has clusters of hydrogen bonds existing in interhelices and extracellular loops; the ORL1 receptor has a possible ligand-binding ""crevice"" situated on the extraside of the transmembrane domains between helices 3, 5, 6, and 7, which is partially covered by the extracellular loop 2 (EL-2); The binding cavity may consist of a ""highly conserved region"" involving the residues of Asp130, Tyr131, and an outer ""conservatively variable region"" containing the residues near the interface of transmembrane (TM) helices-EL loops; The molecular model obtained is qualitatively consistent with ligand affinities, hybrid peptide studies, and other experimental data. CONCLUSION: The structural model of ORL1 receptor from this study is helpful for clarifying experimental observations of ligands interacting with opioid receptors, and for designing new biological investigations."

Density Functional Theory (DFT) Study on the Interaction of Ammonium (NH4+) and Aromatic Nitrogen Heterocyclics

Abstract: A DFT calculation was performed at the B3LYP/6-31G* level on the complexes formed by NH4+ and aromatic nitrogen heterocyclics, viz. pyrrole, imidazole, pyridine and indole, in order to investigate the mechanism and complexity of the interaction between the ammonium group and the aromatic heterocyclic in biomacromolecules. The optimized geometries suggested that there are two different types of complexes: one is a cation–π complex and the other is a hydrogen bond complex. A cation–π complex will be formed if the heteroatom has no localized lone-pair electrons. A hydrogen bond complex will be formed by proton transfer from NH4+ to the heteroatom if the heteroatom has localized lone-pair electrons. In the case of the cation–π complex, the predicted geometries, atomic charges and thermodynamic parameters revealed that ammonium binds more strongly to heterocyclics than it binds to benzene. The calculated orbital coefficient and the optimized structures implied that NH4+ interacts with the π electrons of the CC bond of heterocyclics to form a cation–π complex mainly through one hydrogen atom. Regarding the hydrogen bond complex, although the calculated binding strength is similar to that for the cation–π complex, the ΔH of the whole reaction process suggested that the formation of the hydrogen bond complex is favorable to the stability of the whole system. Calculated IR spectra showed that three groups of new bands appear when NH4+ binds to heterocyclics. Normal mode analysis showed that these new bands are all related to the relative motion of the two parts in the formed complexes. All these results suggest that the NH4+–heterocyclic system is a better model for studying the nature and complexity of the interaction between the ammonium group and the aromatic ring structure in biomolecules.