Alya A. Arabi

Electron-density descriptors as predictors in quantitative structure–activity/property relationships and drug design

The use of electron density-based molecular descriptors in drug research, particularly in quantitative structure--activity relationships/quantitative structure--property relationships studies, is reviewed. The exposition starts by a discussion of molecular similarity and transferability in terms of the underlying electron density, which leads to a qualitative introduction to the quantum theory of atoms in molecules (QTAIM). The starting point of QTAIM is the topological analysis of the molecular electron-density distributions to extract atomic and bond properties that characterize every atom and bond in the molecule. These atomic and bond properties have considerable potential as bases for the construction of robust quantitative structure--activity/property relationships models as shown by selected examples in this review. QTAIM is applicable to the electron density calculated from quantum-chemical calculations and/or that obtained from ultra-high resolution x-ray diffraction experiments followed by nonspherical refinement. Atomic and bond properties are introduced followed by examples of application of each of these two families of descriptors. The review ends with a study whereby the molecular electrostatic potential, uniquely determined by the density, is used in conjunction with atomic properties to elucidate the reasons for the biological similarity of bioisosteres.

Nonempirical density-functional theory for van der Waals interactions

In previous work, Kannemann and Becke [J. Chem. Theory Comput. 5, 719 (2009) and J. Chem. Theory Comput. 6, 1081 (2010)] have demonstrated that the generalized gradient approximations (GGAs) of Perdew and Wang for exchange [Phys. Rev. B 33, 8800 (1986)] and Perdew, Burke, and Ernzerhof for correlation [Phys. Rev. Lett. 77, 3865 (1996)], plus the dispersion density functional of Becke and Johnson [J. Chem. Phys. 127, 154108 (2007)], comprise a nonempirical density-functional theory of high accuracy for thermochemistry and van der Waals complexes. The theory is nonempirical except for two universal cutoff parameters in the dispersion energy. Our calculations so far have been grid-based and have employed the local density approximation (LDA) for the orbitals. In this work, we employ orbitals from self-consistent GGA calculations using Gaussian basis sets. The results, on a benchmark set of 65 van der Waals complexes, are similar to our grid-based post-LDA results. This work sets the stage for van der Waals f...

Distribution of heavy metals in the coastal area of Abu Dhabi in the United Arab Emirates

Fifty-seven sediment samples were collected from Abu Dhabi coastal area, United Arab Emirates (UAE). The concentrations of heavy metals including antimony, arsenic, barium, cadmium, cobalt, copper, mercury, lead, molybdenum, nickel and zinc were obtained using Inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) and X-ray fluorescence. Heavy metal contaminations in Abu Dhabi had increased since 2004. Nevertheless, the enrichment factors, geoaccumulation indices and the pollution load index of 0.3 showed no pollution with any of the measured metals except arsenic.

Regional effects of streptozotocin-induced diabetes on shortening and calcium transport in epicardial and endocardial myocytes from rat left ventricle

In the heart, the left ventricle pumps blood at higher pressure than the right ventricle. Within the left ventricle, the electromechanical properties of ventricular cardiac myocytes vary transmurally and this may be related to the gradients of stress and strain experienced in vivo across the ventricular wall. Diabetes is also associated with alterations in hemodynamic function. The aim of this study was to investigate shortening and Ca2+ transport in epicardial (EPI) and endocardial (ENDO) left ventricular myocytes in the streptozotocin (STZ)‐induced diabetic rat. Shortening, intracellular Ca2+ and L‐type Ca2+ current (ICa,L) were measured by video detection, fura‐2 microfluorimetry, and whole‐cell patch clamp techniques, respectively. Time to peak (TPK) shortening was prolonged to similar extents in ENDO and EPI myocytes from STZ‐treated rats compared to ENDO and EPI myocytes from controls. Time to half (THALF) relaxation of shortening was prolonged in ENDO myocytes from STZ‐treated rats compared to ENDO controls. TPK Ca2+ transient was prolonged in ENDO myocytes from STZ‐treated rats compared to ENDO controls. THALF decay of the Ca2+ transient was prolonged in ENDO myocytes from STZ‐treated rats compared to ENDO controls. Sarcoplasmic reticulum (SR) fractional release of Ca2+ was reduced in EPI myocytes from STZ‐treated rats compared to EPI controls. ICa,L activation, inactivation, and recovery from inactivation were not significantly altered in EPI and ENDO myocytes from STZ‐treated rats or controls. Regional differences in Ca2+ transport may partly underlie differences in ventricular myocyte shortening across the wall of the healthy and the STZ‐treated rat left ventricle.

Electrostatic potentials and average electron densities of bioisosteres in methylsquarate and acetic acid

BACKGROUND The bioisosterism in -CO2H and -C4HO3 is exploited using the quantum theory of atoms in molecules and molecular electrostatic potentials (ESP). RESULTS & DISCUSSION Bioisosteres in methylsquarate and acetic acid, in the neutral/anionic forms, have average electron densities that differ by less than 2% (i.e., ∼0.01 atomic units) while irrespective of the capping group. The topography of the ESP reveals similarities in the case of the neutral species but not in the anionic forms. CONCLUSION The nonclassical bioisosteres in methylsquarate and acetic acid have average electron densities that are similar and relatively insensitive to the ionization state (neutral or anionic) or its studied capping group (H, CH3, Cl or phenyl). The ESP reveals similarities in the topography of neutral molecules.

Routes to drug design via bioisosterism of carboxyl and sulfonamide groups

AIM The similarity in the biological function of the bioisosteric pair, carboxyl and sulfonamide functional groups, is studied using the quantitative tool, average electron density of the bioisosteric moiety in drug molecules and the qualitative tool, electrostatic potential. Results/methodology: Five different capping groups (methyl, phenyl, chlorine, hydrogen and amine) were considered to investigate the effect of the environment on the properties of the bioisosteres. The molecules were considered in their neutral and anionic forms to account for the change in pH depending on the medium of the drug-receptor interactions. CONCLUSION The new developed approach, average electron density, is not only advantageous as a qualitative descriptor, it is also more consistent compared with the conventionally accepted method, electrostatic potential, especially for the anions.

Evaluating dispersion forces for optimization of van der Waals complexes using a non-empirical functional.

Modelling dispersion interactions with traditional density functional theory (DFT) is a challenge that has been extensively addressed in the past decade. The exchange-dipole moment (XDM), among others, is a non-empirical add-on dispersion correction model in DFT. The functional PW86+PBE+XDM for exchange, correlation and dispersion, respectively, compromises an accurate functional for thermochemistry and for van der Waals (vdW) complexes at equilibrium and non-equilibrium geometries. To use this functional in optimizing vdW complexes, rather than computing single point energies, it is necessary to evaluate accurate forces. The purpose of this paper is to validate that, along the potential energy surface, the distance at which the energy is minimum is commensurate with the distance at which the forces vanish to zero. This test was validated for 10 rare gas diatomic molecules using various integration grids and different convergence criteria. It was found that the use of either convergence criterion, 10−6 or 10−8, in Gaussian09, does not affect the accuracy of computed optimal distances and binding energies. An ultra-fine grid needs to be used when computing accurate energies using generalized gradient approximation functionals. This article is part of the themed issue ‘Multiscale modelling at the physics–chemistry–biology interface’.

Effects of Intense Electric Fields on the Double Proton Transfer in the Watson–Crick Guanine–Cytosine Base Pair

The double proton transfer reaction in the guanine-cytosine (GC) base pair is studied, using density functional theory, to understand the chances of mutations under the effect of uniform electric fields in the order of 108 to 109 V m-1. On the basis of potential energy surfaces, reaction Gibbs energies, equilibrium constants, imaginary frequencies, forward and reverse barrier heights, tunneling-corrected rate constants, half-lives of the forward and reverse reactions, percent tautomerization, and Boltzmann distributions, it was found that fields ≥+3.60 × 109 V m-1 facilitate the mutation in the GC base pair and reduce the rectification of point mutations. Fields applied along the double proton transfer in the - x (defined in the C to G direction) direction favor the canonical over the rare tautomers. Tunneling-corrected rate constants of the forward reaction increase exponentially with stronger fields in the - x direction and follow a Gaussian curve for the reverse reaction.