William H. Shelver

Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction.

Docking of metalloproteinase inhibitors remains a challenge due to the zinc multiple coordination geometries and the lack of appropriate force field parameters to model the metal/ligand interactions. In this study, we explore the docking accuracy and scoring reliability for the docking of matrix metalloproteinase (MMP) inhibitors using AutoDock 3.0. Potential problems associated with zinc ion were investigated by docking 16 matrix metalloproteinase ligands to their crystal structures. A good coordination between the zinc binding group (ZBG) and the zinc was shown to be a prerequisite for the ligand to fit the binding site. A simplex optimization of zinc parameters, including zinc radius, well depth, and zinc charges, was performed utilizing the 14 MMP complexes with good docking. The use of optimized zinc parameters (zinc radius: 0.87 A; well depth: 0.35 kcal/mol; and zinc charges: +0.95 e) shows improvement in both docking accuracy at the zinc binding site and the prediction of binding free energies. Although further improvement in the docking procedure, particularly the scoring function is needed, optimization of zinc parameters provides an efficient way to improve the performance of AutoDock as a drug discovery tool.

Application of Artificial Neural Networks in the Optimization of HPLC Mobile-Phase Parameters

The prediction capability of forward feed neural networks was tested ? computer generated capacity factors. The capacity factors were simulate from equations reflecting the contribution of mobile phase changes in pH organic modifier concentration, and ion-pair concentration. Simulated data allows an appropriate experimental design which assures the training of the network does not involve memorization but guarantees the network was generalize. The use of different mathematical forms to calculate the behaviour of capacity factor with changes in pH, methanol concentratior and ion-pair concentration permitted us to explore the capability of neural networks to fit a variety of curves. Each of the independent variables was studied separately, and then in combination. The effect of variabl transformation played a very important role in effective training of th network. The neural network output equations were used to formulate nonlinear regression problem and the behaviour of this model was compare to the neural network system. When the neural network systems had only sufficient processing units needed to solve the problem, nonlinear regressio models and neural networks arrived at identical solutions. When the network contained excessive neurons, nonlinear regression techniques were unstable, having high intraparameter correlations and showing matrix singularity.

Semiempirical molecular orbital calculations on the role of hydrogen bonding in the structure of bilirubin dianion

Abstract Semiempirical molecular orbital methods were utilized in the computation of a fully optimized structure of bilirubin dianion. The structure obtained from the theoretical calculations agreed well with the structure determined from X-ray crystallographic studies. The intramolecular hydrogen bond distance parameters (distance) corresponded with the experimentally determined distances, but the calculated values demonstrated interesting differences between the two hamiltonians used in the computations. Calculations based on the PM3 hamiltonian placed the hydrogens substantially closer to the acceptor oxygen than the corresponding calculations based on the AM1 hamiltonian. The heavy atoms forming the hydrogen bond were also much closer in the PM3 results. Conformational studies were carried out using the AM1 hamiltonian while rotating the central C9-C10 bond, which causes severe distortion to the “ridge tile” structure found in the experimentally determined structures. The hydrogen bonds exhibited remarkable tenacity during rotation of the C9-C10 bond, resisting breaking until the molecule has rotated to the point where the molecule will invert creating the other enantiomeric form.

Conformational studies of imiloxan and imiloxan cation using AM1 and PM3 semiempirical molecular orbital methods

Abstract Conformational studies of the α 2B adrenergic receptor antagonist, imiloxan, were performed using the AM1 and PM3 semiempirical molecular orbital methods. Although the two methods gave similar results, crucial differences were observed. The energy-bond rotation profiles were similar for the two molecular orbital methods, but small differences in these calculations produced substantial differences in the conformers found at the various energy minima. Electrostatic interactions between the imidazoline nitrogens and the dioxane oxygens are decisive in determining the Conformational stability of both the cation and the neutral molecule. The differences between the hamiltonians were apparent in calculations involving the charged cation where the electrostatic interactions stabilize certain conformations and the neutral molecule where the electrostatic interactions are repulsive. Calculations using the AM1 hamiltonian favored conformers with a hydrogen bond, whereas the PM3 calculations gave both nitrogens a positive charge and would favor those conformers in which either one or the other nitrogen was close to the negative oxygen. Although the free base is electrically neutral, the stable conformers showed the importance of the electrostatic interactions caused by the asymmetrical charge distribution around the hetero atoms. Comparison of the molecular orbital structures with the experimental X-ray structure showed that the experimental structure corresponded with a theoretical conformer found at one of the local energy minima rather than the structure found at the global minimum. Imiloxan has a number of conformers at low energy local minima with energies near the global minimum. Therefore, the appearance of a local rather than global minimum energy structure as the X-ray structure is not surprising. These studies demonstrated that electrostatic interactions will likely play an important role in the drug-receptor complex responsible for the pharmacological activity of imiloxan.

Control of Retention Times in the Ion-Paired liquid chromatographic analysis of Bilirubin

Abstract Fluctuations in bilirubin levels are biologically significant and the development of simple, reliable, and flexible chromatographic analyses are required for many research fields. Bilirubins short retention time using reverse phase HPLC combined with the presence of acidic groups on bilirubin suggests ion-paired chromatography would produce the desired analytical procedures. Chromatography using dibutylamine as the ion-pair reagent proved to be successful and the capacity factor of bilirubin was reproducibly controlled by the concentration of dibutylamine, pH, and per cent of methanol in the mobile phase. The results, analyzed by a multilinear regression analysis, produced a mathematical model which calculated the capacity factor based on the dibutylamine concentration, methanol concentration and the hydrogen ion concentration. The analytical system was flexible, reproducible and easy to use. Manipulation of these factors should allow the facile separation of bilirubin from other similar compounds.

Mathematical modeling of various amines in the ion-paired liquid chromatographic analysis of bilirubin

Abstract The use of amines as ion-paired agents for bilirubin is explored. The effect of amine type, amine concentration, hydrogen ion concentration, and methanol concentration are determined and modeled by equations. The ability to adjust the capacity factor using multiple variations of the mobile phase should be useful in optimizing the separation of bilirubin from other components in various biological and theoretical studies of this interesting bile pigment.