Selection of appropriate training and validation set chemicals for modelling dermal permeability by U-optimal design

Quantitative structure-activity relationship (QSAR) models are being used increasingly in skin permeation studies. The main idea of QSAR modelling is to quantify the relationship between biological activities and chemical properties, and thus to predict the activity of chemical solutes. As a key step, the selection of a representative and structurally diverse training set is critical to the prediction power of a QSAR model. Early QSAR models selected training sets in a subjective way and solutes in the training set were relatively homogenous. More recently, statistical methods such as D-optimal design or space-filling design have been applied but such methods are not always ideal. This paper describes a comprehensive procedure to select training sets from a large candidate set of 4534 solutes. A newly proposed ‘Baynes’ rule’, which is a modification of Lipinski's ‘rule of five’, was used to screen out solutes that were not qualified for the study. U-optimality was used as the selection criterion. A principal component analysis showed that the selected training set was representative of the chemical space. Gas chromatograph amenability was verified. A model built using the training set was shown to have greater predictive power than a model built using a previous dataset [1].     

Solubility products for aminocarboxylate ligands: determination, validation and speciation uses

A method combining glass electrode potentiometry and computer simulation of speciation is described and used to determine the solubility product for S,S′-ethylenediamine disuccinate (EDDS) (also known as ethylenediiminodibutanedioic acid). This previously unpublished constant is validated by re-measuring K_sp for isomeric EDTA⁴⁻·H₄⁺ and by a linear free energy relationship. For EDDS⁴⁻·H₄⁺, log K_sp=−25.75±0.30.     

Stabilized phosphatidylinositol-5-phosphate analogues as ligands for the nuclear protein ING2: chemistry, biology, and molecular modeling

The interaction of PtdIns(5)P with the tumor suppressor protein ING2 has been implicated in the regulation of chromatin modification. To enhance the stability of PtdIns(5)P for studies of the biological role in vivo, two phosphatase-resistant moieties were used to replace the labile 5-phosphate. The total asymmetric synthesis of the 5-methylenephosphonate (MP) and 5-phosphothionate (PT) analogues of PtdIns(5)P is described herein, and the resulting metabolically stabilized lipid analogues were evaluated in three ways. First, liposomes containing either the dioleoyl MP or PT analogues bound to recombinant ING2 similar to liposomes containing dipalmitoyl PtdIns(5)P, indicating that the replacement of the hydrolyzable 5-phosphate group does not compromise the binding. Second, the dioleoyl MP and PT PtdIns(5)P analogues were equivalent to dipalmitoyl PtdIns(5)P in augmenting cell death induced by a DNA double-strand break in HT1080 cells. Finally, molecular modeling and docking of the MP or PT analogues to the C-terminus PtdInsP-binding region of ING2 (consisting of a PHD finger and a polybasic region) revealed a number of complementary surface and electrostatic contacts between the lipids and ING2.     

Charge-conserving electron density averaging for a set of nuclear configurations

The Löwdin-Inverse Löwdin Transformation (LILT) technique combined with the Diophantine Density Matrix Purification (DDMP) method is suggested for a charge-preserving density averaging approach for a range of nuclear configurations.     

Rational design, synthesis, and application of a new receptor for the molecular recognition of tricarboxylate salts in aqueous media

A rational design of a tripodal receptor for the molecular recognition of tricarboxylate salts in aqueous media, based on squaramide, has been performed using high-level DFT calculations (RI-BP86/SVP level of theory) in solution using the COSMO treatment, including some preliminary ab initio calculations at the higher RI-MP2/TZVP level of theory, comparing the ability of squaramide to bind carboxylate salts with two widely used guanidinium salts. The tripodal receptor has been synthesized using a new methodology that has been recently reported by some of us, and its capability of recognizing several mono-, di-, and tricarboxylate salts has been studied experimentally by means of microcalorimetry experiments in a very high competitive media, H(2)O:EtOH 1:3. These experiments give enthalpic and entropic data, which are unfortunately scarce in the literature of molecular recognition of anions. Finally, a fluorimetric ensemble of the receptor with fluorescein has been found to be useful for the fluorimetric determination of zinc citrate in a commercial toothpaste using competition assays.     

Complexation reactions,electronic properties,and reactivity descriptors of cysteamine-based ligands in aqueous solution: a PCM/DFT study

Computational approaches based on density functional theory (DFT) combined with polarizable continuum model (PCM) of solvation have been used to probe the likelihood of complexation in water between oxo-vanadium(IV) and various medicinal cysteamine-based ligands. The experimental electronic spectra of a complex formed by oxo-vanadium(IV) and penicillamine in water agree well with the theoretical spectra based on the time-dependent density functional theory (TD-DFT) calculations. Among all density functionals adopted, CAM-B3LYP outperforms the others in predicting both structural and spectroscopic properties of oxo-transition metal complexes of cysteamine-based ligands. A variety of chelation behaviors have been found for the ligands tested, depending on the choice of substituent added to the cysteamine backbone. Solvation has a great impact on the thermodynamic driving force for cysteine and its derivatives to undergo complexation. In all cases, the thiolate sulfur atom forms stronger coordination bond than either the amine nitrogen or carboxylate oxygen atoms. Based on the thermodynamic and nucleophilicity index calculations, penicillamine has the highest potential to form complex with oxo-vanadium(IV).