Bibliothek

Notizen: Abstract Ab Initio, molecular orbital methods are being used to analyze and interpret structure-activity relationships in anti-inflammatory phenols, benzoates and salicylates. The results show a correlation between the potency of the active compounds as inhibitors of prostaglandin production in cell cultures and the orbital energy of the highest occupied molecular orbital with a correlation coefficient ofr ∼ 0.8. The mode(s) of action and structural requirements of anti-inflammatory, non-narcotic analgesics continues to defy rationalization. Even the most plausible proposed molecular mechanism of their anti-inflammatory action, i.e., inhibition of prostaglandin biosynthesis [1], is still subject to controversy [2, 3]. Therefore other approaches may be fruitful for relating the NSAID's biological activity to molecular structure and properties. One such approach is to relate the biological activity to structural indices obtained from molecular orbital theory. From the results of such quantum chemical calculations it is hoped that deeper insight can be obtained into the NSAID's mode(s) of action by evaluating their dependance on the electronic structure of the biologically active species. A complicating factor in the present studies is that the existence of a specific receptor has not yet been firmly established. For the present work biological activity is defined as the potency of the given compound to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced PGE2 release from macrophages isolated from the peritoneum of young male NMRI mice. For methodological details see Ref. [4]. From about 80 compounds which have been assayed a sample of 30 molecules was selected for quantum chemical study. The sample comprises phenol, benzoic acid, and salicylic acid and their hydroxy, fluoro- and chloro congenrs. All calculations were carried out usingab initio molecular orbital methods with programs developed in this laboratory. The σ and π orbital energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were analyzed for correlation with the potency of 18 (or 17) active molecules. As the correlation coefficients in Table 1 show, the π-HOMO orbital energies exhibit a significant correlation with the pIC50's, whereas the σ-HOMO and the LUMO orbital energies do not. The observed correlation shows that potency increases with increasing π-HOMO orbital energy, i.e., weaker binding of the π-HOMO electrons, which enhances the potential for interaction with specific or non-specific interaction sites. Examination of the correlations reported in Table 1 suggests that the first and second row substituents correlate similarly with the π-HOMO orbital energy, but that the second row group is displaced from the first row group. Separate analysis of the two groups is also given in Table 1. These latter correlation coefficients are about 10% higher than for the whole sample. It is noteworthy that for the other orbital energies the single group correlation coefficients can also be quite high, but that the combined correlation is small to completely random. Three models have been proposed for the cyclooxygenase receptor where the NSAID's carry out their purported inhibitory function [5–7]. Although these models differ considerably in their details, all three include a π-electron interaction (acceptor) region. The present results support the need for such a region and suggest that enhanced ability to donate π-electrons helps increase potency in inhibiting the release of PGE2 in macrophages. A detailed report of this work will be given elsewhere.

Notizen: Abstract A new method is proposed for calculating correlation effects in atomic and molecular systems. The basis of the method is the formulation of a set of partial configuration expansions which yield directly variational orbital correlation corrections which are appropriately summed in order to obtain an estimate of the total correlation energy. This method is applied to the ground state of boron hydride and its cation at the equilibrium distance of BH. The results of the method are compared in detail with independent electron pair results and second order CI results. It is further shown that multiple substitutions are approximately accounted for in this method and the extent to which they are included is compared with other approximations. Finally, three methods of increasing accuracy, aimed at reducing the necessary computational effort, are given for determining the vertical ionization potential. The most economical method yields an IP of 9.70 eV or 0.03 eV less than the experimental IP. Completion of the basis is estimated to improve this value to 9.77 eV.

Notizen: Abstract A new method is proposed for calculating correlation effects in atomic and molecular systems. The basis of the method is the formulation of a set of partial configuration expansions which yield directly variational orbital correlation corrections which are appropriately summed in order to obtain an estimate of the total correlation energy. This method is applied to the ground state of boron hydride and its cation at the equilibrium distance of BH. The results of the method are compared in detail with independent electron pair results and second order CI results. It is further shown that multiple substitutions are approximately accounted for in this method and the extent to which they are included is compared with other approximations. Finally, three methods of increasing accuracy, aimed at reducing the necessary computational effort, are given for determining the vertical ionization potential. The most economical method yields an IP of 9.70 eV or 0.03 eV less than the experimental IP. Completion of the basis is estimated to improve this value to 9.77 eV.

Notizen: An implicit solvent model (ISM) for use in molecular mechanics, Monte Carlo, and molecular dynamics simulations on proteins and nucleic acids is proposed that is based on describing the electrostatic component with a screened Coulomb potential (SCP). The SCP has been extended so that both the electrostatic interaction energies and the self-energy terms are included in the solvation energy where the latter has been calculated from the integral Born equation. In addition, the SCP is generalized to allow an accounting of the positional dependence of the interactions between charges in a dielectric. To test the potential of the method to provide a reliable and fast implicit description of solvent, a parameter set has been determined to calculate hydration free energies of a group of small-molecule analogs for neutral amino acid residues. Comparison of the calculated with experimental hydration energies of 18 molecules yields a correlation greater than 0.99, demonstrating the feasibility of the method to form the basis of an ISM. A parameter set based solely on hydration energies is not sufficient to account for the considerably different physical conditions found for a solute in the protein “solvent.” Methods are explored for further generalizing the parameters to account for macromolecular structure, and it is shown that it may be possible to find a positional function of the coordinates that correlates well with the fraction of each amino acid residue buried in the macromolecule. Such a function would reduce computing time by replacing the need for repetitive calculations of the solvent-accessible surface area (and its derivatives in the case of molecular dynamics simulations) with a simple function of the coordinates.   © 1998 John Wiley & Sons, Inc. Int J Quant Chem 69: 57-64, 1998

Notizen: A series of computer simulations has been carried out on bovine pancreatic trypsin inhibitor using various models to mimic the effects of explicit bulk solvent on the structure of the protein. The solvent properties included are the polarization of the solute by the polar bulk solvent and the restraining effect on the motional freedom of the solute due to frictional drag at the solvent-protein surface interface. The former has been included by using a distance-dependent dielectric permittivity to screen the electrostatic interactions, whereas the latter is simulated by adding a limited number of solvent molecules near the protein surface. To achieve the proper mobility of the water molecules, their motion was restrained by adding a harmonic restraining force. It was found that a very small force constant was sufficient to model the static and dynamical behavior of the fully solvated solute, but that it was necessary to include enough explicit waters to occupy the first solvation shell. © 1992 John Wiley & Sons, Inc.