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T R Stouch

Publications and source records attributed to T R Stouch.

8 recordsLinked to original sources
PubMed1996

Drug-membrane interactions studied by molecular dynamics simulation: size dependence of diffusion.

Bioavailability, largely due to membrane permeation, is an important step in the drug delivery process and therefore drug design. In this study, a series of molecular dynamics simulations (totaling 10's of nanoseconds) of small molecules (varying in size, and functional groups) in lipid bilayer membranes were used to elucidate the mechanism of diffusion of drugs within biomembranes. These simulations accurately reproduce many experimentally observed parameters. The simulations also agree with theory that indicates the lipid bilayer has internal structure that influences the diffusion process and that even within the hydrocarbon regions there are distinct regions between which the rate and mechanism of diffusion varies. In particular, in agreement with experiment and theory the small solutes were found to diffuse by a mechanism different from that of large molecules. These variations are linked to the frequency and size of spontaneously arising voids within the bilayer as well as the rate of torsional isomerization of the hydrocarbon chains.

Biological Availability↗
PubMed1995

Three-dimensional quantitative structure-activity relationships of sulfonamide endothelin inhibitors.

A three-dimensional quantitative structure-activity relationship (QSAR) using steric and electrostatic fields (comparative molecular field analysis, CoMFA) applied to 36 aryl sulfonamides assayed for endothelin receptor subtype-A (ETA) antagonism provided high cross-validation correlations (0.7) and showed promising predictive ability. The results were validated through trials using scrambled activities as well as trials using scrambled orientation of molecules. CoMFA was used to discriminate between alternate hypothetical biologically active conformations. CoMFA was also used to discriminate between two different molecular superpositions representing possible positioning within the receptor binding site. The preferred superposition supports hypotheses that suggest Tyr129 in the ETA receptor as a key residue for antagonist binding. Significant CoMFA results were obtained when crudely optimized geometries and simple charge schemes were used. The results improved on refinement, most substantially with refinement of the atomic charges.

Animals↗
PubMed1993

Solute diffusion in lipid bilayer membranes: an atomic level study by molecular dynamics simulation.

To elucidate the mechanism of solute diffusion through lipid bilayer membranes, nearly 4 ns of molecular dynamics simulations of solutes in phospholipid bilayers was conducted. The study, the first atomic level study of solute diffusion in a lipid bilayer, involved four simulations of an all-atom representation of a fully solvated dimyristoylphosphatidylcholine (DMPC) bilayer in the L alpha phase with benzene molecules as solutes, totaling over 7100 atoms. These simulations agree with experimental evidence that the presence of small solutes does not affect bilayer thickness but does result in slight perturbations in the ordering of the hydrocarbon chains. At room temperature, the benzene molecules have essentially isotropic motion and rotate freely. The rate of translational diffusion varies with position within the bilayer and is faster in the center than near the zwitterionic headgroups and is in excellent agreement with experimental values for the diffusion of small solutes in a bilayer. These simulations have elucidated the mechanism of diffusion in a bilayer to be similar to the "hopping" mechanism found for the diffusion of gases through soft polymers. Jumps of up to 8 A can occur in as little as 5 ps whereas average motions for that time period are only approximately 1.5 A. In many cases, the jumps are moderated by torsional changes in the hydrocarbon chains which serve as "gates" between voids through which the benzene molecules move. Comparison of these simulations with another 1000-ps simulation of benzene in a pure alkane provides evidence that lipid bilayers should not be treated as a homogeneous bulk hydrocarbon phase.

Alkanes↗
PubMed1986

Computer-aided studies of the structure-activity relationships between the structure of some steroids and their antiinflammatory activity.

The relationship between variation in structure and variation in antiinflammatory activity was investigated for 125 steroids whose antiinflammatory activity had previously been determined by using the McKenzie-Stoughton human vasoconstrictor assay. Eighty-eight of the compounds were used in the training stages of analysis. A two-class problem was developed by classifying the compounds as low-to-no potency (37 compounds) or potent-to-very potent (51 compounds) on the basis of their activity relative to that of hydrocortisone butyrate. Thirty-eight different structural variations occurred at six different sites on the steroid nucleus. These variations were coded by a total of 10 descriptors--three indicator descriptors and seven descriptors that coded for the lipophilicity of the substituents at specific sites of variation. Linear discriminant analysis, principal components plots, K nearest neighbor analysis, and statistical measurements of class separation all confirmed that the more potent compounds existed in a region of the data space different from the less potent compounds. This structure-activity relationship was applied to the prediction of the activities of 37 compounds that were not used in the preliminary analysis with good results.

Anti-Inflammatory Agents↗
PubMed1985

Computer-assisted studies of molecular structure-biological activity relationships.

Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conformational analysis and display, quantum mechanical methods, and methods relying on discriminant development and pattern-recognition techniques. Application areas for this technology include drug design, agricultural chemical design, and studies of chemical toxicity and genetic toxicity (mutagenic or carcinogenic potential). These structure-activity methods are introduced, and citations are given. Several current structure-activity relationship (SAR) studies using pattern recognition are presented as examples of typical projects that are feasible with this approach. These include the investigation of a set of 122 antiinflammatory steroids, a study of 153 retinoids for cancer prevention, and a study of chemicals that have been tested in a sister chromatid exchange mutagen screen.

Animals↗
PubMed1985

Computer-assisted studies of molecular structure and genotoxic activity by pattern recognition techniques.

Often a compound's biological activity is determined by complex relationships between its structural components. Such a relationship often can only be adequately described and exploited by multivariate structure-activity relationship (SAR) studies that can deal with many variables simultaneously. Pattern recognition (PR) is a multivariate technique that is well suited for the qualitative, active-inactive, data that is often supplied by biological assays. PR studies of compounds of known activity can yield information that will allow the prediction of the activity of untested compounds. ADAPT is a computerized system that was developed for such PR-SAR studies. A general introduction to this field is presented and the methodology used for such a study is described in the context of an actual study of mutagenic compounds. The data requirements, descriptor generation, and the details of a PR study are discussed. In addition, the example study was chosen to highlight the problems that may occur if a study is not well formulated and carefully executed. Current work and future plans for computerized mutagen screening are discussed.

Computers↗
PubMedDate not supplied

Computer-assisted studies of molecular structure and carcinogenic activity.

Both quantitative and qualitative studies of the structure-activity relationships (SAR) of carcinogenic compounds are discussed. Using the ADAPT software system, examples are given of (1) predicting the gas and liquid chromatographic retention behavior of polycyclic aromatic compounds, (2) predicting the carcinogenicity of N-nitrosamines, and (3) predicting the mutagenic behavior of pesticides and other compounds in short-term test systems. It is concluded that the complexity and lack of understanding of the carcinogenic response should not prevent scientists from searching for useful empirical relationships between molecular structure and carcinogenicity. Computer generated molecular descriptors and statistical and pattern recognition techniques can be useful tools in this research.

Animals↗