Use of density functional calculations to predict the regioselectivity of drugs and molecules metabolized by aldehyde oxidase.

Aldehyde oxidase is a molybdenum hydroxylase that catalyzes the oxidation of aldehydes and nitrogen-containing heterocycles. The enzyme plays a dual role in the metabolism of physiologically important endogenous compounds and the biotransformation of xenobiotics. Using density functional theory methods, geometry optimization of tetrahedral intermediates of drugs and druglike compounds was examined to predict the likely metabolites of aldehyde oxidase.

Empirical regioselectivity models for human cytochromes P450 3A4, 2D6, and 2C9.

Cytochromes P450 3A4, 2D6, and 2C9 metabolize a large fraction of drugs. Knowing where these enzymes will preferentially oxidize a molecule, the regioselectivity, allows medicinal chemists to plan how best to block its metabolism. We present QSAR-based regioselectivity models for these enzymes calibrated against compiled literature data of drugs and drug-like compounds.

Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules.

The affinities of a diverse set of 500 drug-like molecules to cytochrome P450 isoforms 2C9 and 2D6 were measured using recombinant expressed enzyme. The dose-response curve of each compound was fitted with a series of equations representing typical or various types of atypical kinetics. Atypical kinetics was identified where the Akaike Information Criterion, plus other criteria, suggested the kinetics was more complex than expected for a Michaelis-Menten model.

Theoretical examination of Mg(2+)-mediated hydrolysis of a phosphodiester linkage as proposed for the hammerhead ribozyme.

The hammerhead ribozyme is an RNA molecule capable of self-cleavage at a unique site within its sequence. Hydrolysis of this phosphodiester linkage has been proposed to occur via an in-line attack geometry for nucleophilic displacement by the 2'-hydroxyl on the adjoining phosphorus to generate a 2',3'-cyclic phosphate ester with elimination of the 5'-hydroxyl group, requiring a divalent metal ion under physiological conditions. The proposed S(N)2(P) reaction mechanism was investigated using density functional theory calculations incorporating the hybrid functional B3LYP to study this metal ion-dependent reaction with a tetraaquo magnesium (II)-bound hydroxide ion.

The circumsphere as a tool to assess distortion in [4Fe-4S] atom clusters.

The geometry proposition that "four points not in a plane describe one and only one sphere" provides a novel tool for analyzing protein-induced distortions in [4Fe-4S] clusters. A geometrically perfect reference structure comprises interlaced, regular tetrahedra of Fe, S, and S gamma atoms having T(d) symmetry. Three circumspheres are defined by the three sets of four atoms, the circumcenters of which are unique points within the cluster.

Density functional and reduction potential calculations of Fe4S4 clusters.

Density functional theory geometry optimizations and reduction potential calculations are reported for all five known oxidation states of [Fe(4)S(4)(SCH(3))(4)](n)()(-) (n = 0, 1, 2, 3, 4) clusters that form the active sites of iron-sulfur proteins. The geometry-optimized structures tend to be slightly expanded relative to experiment, with the best comparison found in the [Fe(4)S(4)(SCH(3))(4)](2)(-) model cluster, having bond lengths 0.03 A longer on average than experimentally observed.

Metal substitution in the active site of nitrogenase MFe(7)S(9) (M = Mo(4+), V(3+), Fe(3+)).

The unifying view that molybdenum is the essential component in nitrogenase has changed over the past few years with the discovery of a vanadium-containing nitrogenase and an iron-only nitrogenase. The principal question that has arisen for the alternative nitrogenases concerns the structures of their corresponding cofactors and their metal-ion valence assignments and whether there are significant differences with that of the more widely known molybdenum-iron cofactor (FeMoco). Spin-polarized broken-symmetry (BS) density functional theory (DFT) calculations are used to assess which of the two possible metal-ion valence assignments (4Fe(2+)4Fe(3+) or 6Fe(2+)2Fe(3+)) for the iron-only cofactor (FeFeco) best represents the resting state.

Insights into properties and energetics of iron-sulfur proteins from simple clusters to nitrogenase.

Some of the principal physical features of iron-sulfur clusters in proteins are analyzed, including metal-ligand covalency, spin polarization, spin coupling, valence delocalization, valence interchange and small reorganization energies, with emphasis on recent spectroscopic and theoretical work. The current state of structural, spectroscopic, and computational knowledge for the iron-sulfur clusters in the nitrogenase iron and iron-molybdenum proteins is examined by comparison and contrast to 'simpler' ironclusters. The differing interactions of the nitrogenase iron and iron-molybdenum clusters compared with those of other iron-sulfur clusters with the protein and solvent environment are also explored.