Knowledge-Based Expert Systems for Toxicity and Metabolism Prediction: DEREK,StAR and METEOR

Abstract

It has long been recognised that the ability to predict the metabolic fate of a chemical substance and the potential toxicity of either the parent compound or its metabolites are important in novel drug design. The popularity of using computer models as an aid in this area has grown considerably in recent years.

LHASA Limited has been developing knowledge-based expert systems for toxicity and metabolism prediction in collaboration with industry and regulatory authorities. These systems, DEREK, StAR and METEOR, use rules to describe the relationship between chemical structure and either toxicity in the case of DEREK and StAR, or metabolic fate in the case of METEOR.

The rule refinement process for DEREK often involves assessing the predictions for a novel set of compounds and comparing them to their biological assay results as a measure of the system's performance. For example, 266 non-congeneric chemicals from the National Toxicology Program database have been processed through the DEREK mutagenicity knowledge base and the predictions compared to their Salmonella typhimurium mutagenicity data. Initially, 81 of 114 mutagens (71%) and 117 of 152 non-mutagens (77%) were correctly identified. Following further knowledge base development, the number of correctly identified mutagens has increased to 96 (84%). Further work on improving the predictive capabilities of DEREK, StAR and METEOR is in progress.     

Correlations of ion structure with multiple fragmentation pathways arising from collision‐induced dissociations of selected α‐hydroxycarboxylic acid anions

Under conditions of collision‐induced dissociation (CID), anions of α‐hydroxycarboxylic acids usually fragment to yield the distinctive hydroxycarbonyl anion (m/z 45) and/or the complementary product anion formed by neutral loss of formic acid (46 u). Further support for the known two‐step mechanism, involving an ion‐neutral complex for the formation of the hydroxycarbonyl anion from the carboxyl group, is herein provided by tandem mass spectrometric results and density functional theory computations on the glycolate, lactate and 3‐phenyllactate ions. A fourth, structurally related α‐hydroxycarboxylate ion, obtained by deprotonation of mandelic acid, showed only loss of carbon dioxide upon CID. Density functional theory computations on the mandelate ion indicated that similar energy inputs were required for a direct, phenyl‐assisted decarboxylation and a postulated novel rearrangement to a carbonate ester, which yielded the benzyl oxide ion upon loss of CO₂. Rearrangement of the glycolate ion led to expulsion of carbon monoxide, whereas the 3‐phenyllactate ion showed the loss of water and formation of the benzyl anion and the benzyl radical as competing processes. The fragmentation pathways proposed for lactate and 3‐phenyllactate are supported by isotopic labeling. The relative computed energies of saddle points and product ions for all proposed fragmentation pathways are consistent with the energies supplied during CID experiments and the observed relative intensities of product ions. The diverse reaction pathways characterized for this set of four α‐hydroxycarboxylate ions demonstrate that it is crucial to understand the effects of structural variations when attempting to predict the gas‐phase reactivity and CID spectra of carboxylate ions. Copyright © 2013 John Wiley & Sons, Ltd.     

Heme charge-transfer band III is vibronically coupled to the Soret band

A complete resonance Raman excitation profile of the heme charge-transfer band known as band III is presented. The data obtained throughout the near-infrared region show preresonance with the Q-band, but the data also clearly show the enhancement of a number of modes in the spectral region of band III. Only nontotally symmetric modes are observed to have resonance enhancement in the band III region. The observed resonance enhancements in modes of B(1g) symmetry are compared with the enhancements of those same modes in the excitation profiles of the Q-band of deoxy myoglobin, also presented here for this first time. The Q-band data agree well with the theory of vibronic coupling in metalloporphyrins (Shelnutt, J. A. J. Chem. Phys. 1981, 74, 6644-6657). The strong vibronic coupling of the Q-band of the deoxy form of hemes is discussed in terms of the enhancement of modes with both B(1g) and A(2g) symmetry. The comparison between the Q-band and band III reveals that, consistent with the theory, only modes of B(1g) symmetry are enhanced in the vicinity of band III. These results show that band III is vibronically coupled to the Soret band. The coupling of band III to modes with strong rhombic distortion of the heme macrocycle calls into question the hypothesis that the axial iron out-of-plane displacement is primarily responsible for the structure-dynamics correlations observed in myoglobin.     

New pyridone approach: total synthesis of mappicine ketone (nothapodytine B)

A novel synthesis of mappicine ketone, which possesses strong selective activity against the herpes viruses HSV-1 and HSV-2, including those Acyclovir-resistant, and human cytomegalovirus (HCMV) has been efficiently accomplished. The synthesis highlights a new pyridone approach that effectively combines a double, intramolecular Michael addition in a conjugated ester-conjugated amide with oxidation-decarboxylation of the resulting piperidone.     

The connection between the thermodynamics of chemisorption on semiconductor surfaces and surface scattering of carriers

An explicit theoretical relation is derived which connects the thermodynamics of chemisorption on semiconductor surfaces with the scattering rate of conduction and valence band carriers by charges localized in the chemisorption bonds.     

A unified theory of Stark broadening for hydrogenic ions—III: Results for He II Lyman-α

Calculations have been performed for He II Lyman-α using a previously developed theory (Papers I and II in this series) in which the effect of time-ordering in the required time development operator is retained. Representative results are given for an electron density of 10¹⁷ cm^-3 and a temperature of 40,000°K. Compared with non-time ordered results, these profiles are about 17% lower at line center and up to 16% higher in the wings. In addition, since the perturbing electron is speeded up by the Coulomb attraction, in comparison with neutral hydrogen the static results are not obtained until much further into the line wings. Comparison is also made to the calculations of Kepple for which good agreement is obtained, except near the line center where the difference approaches 25%.     

Epitaxial crystal growth by sputter deposition: Applications to semiconductors. Part I

The process of sputtering may be defined as the ejection of target particles due to the impingement of energetic projectile particles. The use of sputtered species as source material to deposit thin films was first reported in the literature in 1852¹ and has since enjoyed several periods of scientific and commercial interest interspersed with periods of disrepute. However, it is only recently that sufficient understanding of the complex processes occurring during, and simultaneously with. ion bombardment of solid surfaces has developed to result in the ability to reproducably and controllably use sputter deposition to grow high quality single crystal semiconducting thin films. The evolution of the branch of science concerned with ion‐surface interactions has been facilitated by the parallel development of ultra high vacuum technology and highly sensitive microanalytic techniques for identifying the state of scattered particles, sputtered species, and implanted material.