RESUMEN
This paper addresses the issue of the ultrasound effects upon the creep deformation of metals with different levels of stacking fault energy. The influence of preliminary ultrasound irradiation time upon the steady state creep rate is considered. Synthetic theory of irrecoverable deformation is taken as a mathematical apparatus. The analytical results show good agreement with experimental data.
Asunto(s)
Ondas de Choque de Alta Energía , Metales/química , Metales/efectos de la radiación , Modelos Químicos , Sonicación/métodos , Simulación por Computador , Módulo de Elasticidad/efectos de la radiación , Dureza/efectos de la radiación , Resistencia a la Tracción/efectos de la radiación , Viscosidad/efectos de la radiaciónRESUMEN
In the presented work, a modeling of ultrasonic hardening and softening has been carried out. The analytical model is constructed by the generalization of the synthetic theory of plastic deformation. A new term, ultrasonic defect intensity, is being introduced so that the phenomenon of both hardening and softening is described by the uniform system of constitutive equations.
Asunto(s)
Ultrasonido , Acústica , Matemática , Modelos TeóricosRESUMEN
Combinatorial chemistry and high-throughput screening are revolutionizing the process of lead discovery in the pharmaceutical industry. Large numbers of structures and vast quantities of biological assay data are quickly being accumulated, overwhelming traditional structure/activity relationship (SAR) analysis technologies. Recursive partitioning is a method for statistically determining rules that classify objects into similar categories or, in this case, structures into groups of molecules with similar potencies. SCAM is a computer program implemented to make extremely efficient use of this methodology. Depending on the size of the data set, rules explaining biological data can be determined interactively. An example data set of 1650 monoamine oxidase inhibitors exemplifies the method, yielding substructural rules and leading to general classifications of these inhibitors. The method scales linearly with the number of descriptors, so hundreds of thousands of structures can be analyzed utilizing thousands to millions of molecular descriptors. There are currently no methods to deal with statistical analysis problems of this size. An important aspect of this analysis is the ability to deal with mixtures, i.e., identify SAR rules for classes of compounds in the same data set that might be binding in different ways. Most current quantitative structure/activity relationship methods require that the compounds follow a single mechanism. Advantages and limitations of this methodology are presented.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Industria Farmacéutica , Relación Estructura-ActividadRESUMEN
The identification of three-dimensional pharmacophores from large, heterogeneous data sets is still an unsolved problem. We developed a novel program, SCAMPI (statistical classification of activities of molecules for pharmacophore identification), for this purpose by combining a fast conformation search with recursive partitioning, a data-mining technique, which can easily handle large data sets. The pharmacophore identification process is designed to run recursively, and the conformation spaces are resampled under the constraints of the evolving pharmacophore model. This program is capable of deriving pharmacophores from a data set of 1000-2000 compounds, with thousands of conformations generated for each compound and in less than 1 day of computational time. For two test data sets, the identified pharmacophores are consistent with the known results from the literature.
Asunto(s)
Bases de Datos Factuales , Diseño de Fármacos , Programas Informáticos , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Técnicas Químicas Combinatorias , Conformación Molecular , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Diseño de Software , Relación Estructura-ActividadRESUMEN
A series of optically pure 2-[substituted-3-aminopropynyl]pyrrolidine derivatives, which are restricted-rotation analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5, compound 1), have been prepared from d- and l-proline. The compounds when tested in a series of in vitro muscarinic assays [[3H]CD (cortex), [3H]QNB (cortex), [3H]PZ (cortex), [3H]QNB (heart), [3H]QNB + GppNHp (heart)] were found to have weaker muscarinic properties than compound 1. The decrease in affinity was attributed to the increased size of the molecule resulting from the addition of a methylene group to form the pyrrolidine ring. The use of optically active compounds provided a more detailed examination of the complex pharmacological effects of the flexible muscarinic agent 1. The R enantiomers in the acetamide derivatives 12b, 12d, and 12f had a 5-10-fold greater affinity for the muscarinic receptor than the corresponding S enantiomers. A 5-fold difference or less found in the (R)- and (S)-carbamate derivatives 9, 15, and 16 suggested close overlap of the two enantiomers in the receptor binding domain. The affinity differences found in the enantiomeric acetamido derivatives when compared to those of the carbamate analogues may be the result of limited rotation of the acetamido group.
Asunto(s)
Parasimpaticomiméticos/química , Pirrolidinas/química , Pirrolidinas/síntesis química , Animales , Unión Competitiva , Corteza Cerebral/metabolismo , Fenómenos Químicos , Química , Dioxolanos/metabolismo , Guanilil Imidodifosfato/farmacología , Espectroscopía de Resonancia Magnética , Masculino , Conformación Molecular , Estructura Molecular , Miocardio/metabolismo , Parasimpaticomiméticos/metabolismo , Parasimpaticomiméticos/farmacología , Pirenzepina/metabolismo , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Quinuclidinil Bencilato/metabolismo , Ratas , Ratas Endogámicas , Receptores Muscarínicos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Pharmacophores, three-dimensional arrangements of chemical groups essential for biological activity, are being proposed in increasing numbers. We have developed a system to search data bases of three-dimensional coordinates for compounds that contain a particular pharmacophore. The coordinates can be derived from experiment (e.g., Cambridge Crystal Database) or be generated from data bases of connection tables (e.g., Cyanamid Laboratories proprietary compounds) via the program CONCORD. We discuss the results of searches for three sample pharmacophores. Two have been proposed by others based on the conformational analysis of active compounds, and one is inferred from the crystal structure of a protein-ligand complex. These examples show that such searches can identify classes of compounds that are structurally different from the compounds from which the pharmacophore was derived but are known to have the appropriate biological activity. Occasionally, the searches find bond "frameworks" in which the important groups are rigidly held in the proper geometry. These may suggest new structural classes for synthesis.