In silico discovery of beta-secretase inhibitors

Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the beta-amyloid precursor protein is initiated by beta-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1. More than 300,000 small molecules were docked and about 15,000 prioritized according to a linear interaction energy model with evaluation of solvation by continuum electrostatics. Eighty-eight compounds were tested in vitro, and 10 of them showed an IC(50) value lower than 100 microM in a BACE-1 enzymatic assay. Interestingly, the 10 active compounds shared a triazine scaffold. Moreover, four of them were active in an assay with mammalian cells (EC(50) < 20 microM), indicating that they are cell-permeable. Therefore, these triazine derivatives are very promising lead candidates for BACE-1 inhibition. The discoveries of this series and two other series of nonpeptidic BACE-1 inhibitors demonstrate the usefulness of our in silico high-throughput screening approach.     

An intramolecularly self-templated synthesis of macrocycles: self-filling effects on the formation of prismarenes

Ethyl- and propyl-prism[6]arenes are obtained in high yields and in short reaction times, independent of the nature and size of the solvent, in the cyclization of 2,6-dialkoxynaphthalene with paraformaldehyde. PrS[6]Et or PrS[6]nPr adopt, both in solution and in the solid state, a folded cuboid-shaped conformation, in which four inward oriented alkyl chains fill the cavity of the macrocycle. On these bases, we proposed that the cyclization of PrS[6]Et or PrS[6]nPr occurs through an intramolecular thermodynamic self-templating effect. In other words, the self-filling of the internal cavity of PrS[6]Et or PrS[6]nPr stabilizes their cuboid structure, driving the equilibrium toward their formation. Molecular recognition studies, both in solution and in the solid state, show that the introduction of guests into the macrocycle cavity forces the cuboid scaffold to open, through an induced-fit mechanism. An analogous conformational change from a closed to an open state occurs during the endo-cavity complexation process of the pentamer, PrS[5]. These results represent a rare example of a thermodynamically controlled cyclization process driven through an intramolecular self-template effect, which could be exploited in the synthesis of novel macrocycles.

Ethyl- and propyl-prism[6]arenes are obtained by an intramolecular thermodynamic self-template effect: the self-filling of the internal cavity stabilizes their cuboid structure, driving the equilibrium toward their formation.     

Structure‐based ligand design by a build‐up approach and genetic algorithm search in conformational space

Program to engineer peptides (PEP) is a build‐up approach for ligand docking and design with implicit solvation. It requires the knowledge of a seed from which it iteratively grows polymeric ligands consisting of any type of amino acid, i.e., natural and/or nonnatural from a user‐defined library. At every growing step, a genetic algorithm is used for conformational optimization of the last added monomer in the rigid binding site. Pruning is performed at every growing step by selecting sequences according to binding energy with electrostatic solvation. PEP is applied to three members of the caspase family of cysteine proteases using Asp at P₁ as seed. The optimal P₄–P₂ peptide recognition motifs and variants thereof are docked correctly in the active site (backbone root‐mean‐square deviation < 0.9 Å). Moreover, for each caspase, the P₄–P₂ sequences of potent aldehyde inhibitors are ranked among the 15 hits with the most favorable PEP energy. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1956–1970, 2001     

Kinetics and Thermodynamics of Binding of a Model Tripeptide to Teicoplanin and Analogous Semisynthetic Antibiotics

The thermodynamics and kinetics of binding of model tripeptides epsilon-N-acetyl-alpha-N-dansyl-L-Lys-D-Ala-D-Ala (ADLAA) or alpha-N,epsilon-N-diacetyl-L-Lys-D-Ala-D-Ala (AALAA) to teicoplanin (1a) and a series of semisynthetic derivatives with (1b-f) or devoid of (2a-g) the glycidic side arms and modified at the terminal amino acids of the peptide backbone have been studied by fluorescence or UV spectroscopy. The binding process is suggested to occur via a two-step mechanism. The first, fast process is likely governed by an electrostatic interaction between the C- and N-termini of the peptide chain of the substrate and of the antibiotic, respectively, while the second slower one, accounts for the formation of the hydrogen bonds responsible of the major contribution to the overall binding energy. The binding constants with all modified derivatives are smaller than that with native teicoplanin. Larger modification of the overall binding constant are observed when the sugar residues are removed and, to a lower extent, when the N-terminus of the peptide chain is acylated. The kinetic process is very little affected by the modifications introduced.     

Chemistry between magnesium and multiple molecules in tris(8-hydroxyquinoline) aluminum films

Metal organic contacts are at the basis of devices such as organic light emitting diodes (OLEDs). Here, we report a theoretical investigation of the chemical interaction between a Mg atom and an organic film made of tris(8-hydroxyquinoline)aluminum (Alq3) molecules. The latter is modeled either by an isolated molecule or by a bulk crystal. Using first-principles molecular dynamics for structural optimization, we find that an isolated Alq3 molecule and a Mg atom form an ion-pair. However, when the metal atom interacts with molecules in a bulk crystalline environment, we find that an organometallic complex is energetically preferred over the ion-pair. The complex formation is an effect of the environment which makes possible the interaction of the metal atom with several adjacent molecules. Here, our calculated O(1s) and N(1s) core level shifts agree well with recent experimental data on Alq3 films exposed to Mg. Our results resolve the apparent contradiction between experiment and predictions made in previous calculations in which a single Alq3 molecule was used to model a thin film.     

Powder diffraction study of a coordination polymer comprised of rigid building blocks: [Rh2(O2CCH3)4.mu2-Se2C5H8-Se,Se']infinity

The crystal structure of a new hybrid product comprised of two rigid building blocks, namely dirhodium(II) tetraacetate, [Rh(2)(O(2)CCH(3))(4)] (1), and 2,6-diselenaspiro[3.3]heptane, Se(2)C(5)H(8) (2), has been solved ab initio using laboratory source X-ray powder diffraction (XRPD) data. The rigid body refinement approach has been applied to assist in finding an adequate model and to reduce the number of the refined parameters. Complex [Rh(2)(O(2)CCH(3))(4).mu(2)-Se(2)C(5)H(8)-Se,Se'] (3) conforms to the triclinic unit cell with lattice parameters of a = 8.1357(4), b = 8.7736(4), and c = 15.2183(8) A, alpha = 77.417(3), beta = 88.837(3), and gamma = 69.276(4) degrees, V = 989.66(8) A(3), and Z = 2. The centrosymmetric P space group was selected for calculations. The final values of the reduced wR(p), R(p), and chi(2) were calculated at 0.0579, 0.0433, and 5.95, respectively. The structure of 3 is a one-dimensional zigzag polymer built on axial Rh...Se interactions at 2.632(6) A. The 2,6-diselenaspiro[3.3]heptane ligand acts as a bidentate linker bridging dirhodium units via both selenium atoms. The geometrical parameters of individual groups for rigid body refinement have been obtained from X-ray powder data for dirhodium(II) tetraacetate (1) and from single-crystal X-ray diffraction for diselenium molecule 2. The crystal structures of 1 and 2 are reported here for the first time. For 1 indexing based on XRPD data has resulted in the triclinic unit cell P with lattice parameters of a = 8.3392(7), b = 5.2216(5), and c = 7.5264(6) A, alpha = 95.547(10), beta = 78.101(6), and gamma = 104.714(13) degrees, V = 309.51(5) A(3), and Z = 1. The final values were wR(p) = 0.0452, R(p) = 0.0340, and chi(2) = 1.99. The 1D polymeric motif built on axial Rh.O interactions of the centrosymmetric dirhodium units has been confirmed for the solid-state structure of 1. Compound 2,6-diselenaspiro[3.3]heptane (2) conforms to the monoclinic space group P2(1)/c with the unit cell parameters of a = 5.9123(4), b = 19.6400(13), and c = 5.8877(4) A, beta = 108.5500(10) degrees, V = 648.15(8) A(3), and Z = 4.     

Effect of Metal Ions in Organic Synthesis. Part XXX. Synthesis of New 3-Carbonyl- and 3-Carboxy-1-Alkoxycarbonylaminopyrroles from Reaction Catalyzed by Copper(II) Chloride of Alkoxycarbonylazoalkenes with β-Diketones and β-Ketoesters

In the course of our previous investigations, we dealt with the direct synthesis of unknown 1-aminopyrroie derivatives, obtained by reaction of some azoalkenes with B-diketones, 8- ketoesters, or B-ketoamides under copper (II) ionscatalysis. 1-9     

Some properties for quaternionic slice regular functions on domains without real points

The theory of slice regular functions over the quaternions, introduced by Gentili and Struppa in 2007, was born on balls centred in the origin and has been extended to more general domains that intersect the real axis in a work of 2009 in collaboration with Colombo and Sabadini. This hypothesis can be overcome using the theory of stem functions introduced by Ghiloni and Perotti in 2011, in the context of real alternative algebras. In this paper, I will recall the notion and the main properties of stem functions. After that I will introduce the class of slice regular functions induced by stem functions and, in this set, I will extend the identity principle, the maximum and minimum modulus principles and the open mapping theorem. Differences will be shown between the case when the domain does or does not intersect the real axis.