PubMed · 5094945
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W Büchler. 1971. Analytical methods for phosphamidon.. https://doi.org/10.1007/978-1-4615-8473-5_2
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The ability of three-dimensional quantitative structure-activity relationships (QSARs) derived from classical QSAR descriptors and similarity indices to rationalize the activity of 28 N-terminus fragments of tachykinin NK1 receptor antagonists was examined. Two different types of analyses, partial least squares and multiple regression, were performed in order to check the robustness of each derived model. The models derived using classical QSAR descriptors lacked accurate quantitative and predictive abilities to describe the nature of the receptor-inhibitor interaction. However models derived using 3D QSAR descriptors based on similarity indices were both robust and significantly predictive. The best model was obtained through the statistical analysis of molecular field similarity indices (n = 28, r2 = 0.846, r(cv)2 = 0.737, s = 0.987, PRESS = 7.102) suggesting that electronic and size-related properties are the most relevant in explaining the affinity data of the training set. The overall quality and predictive ability of the models applied to the test set appear to be very high, since the predicted affinities of three test compounds agree with the experimentally determined affinities obtained subsequently within the experimental error of the binding data.
The calculation of interaction energies between cellulose trisphenylcarbamate (CTPC) and enantiomers of (+/-)-trans-stilbene oxide (1) and (+/-)-trans-1,2-diphenylcyclopropane (2) was performed using QUANTA/CHARMm and MOLECULAR INTERACTION programs to gain an insight into the chiral recognition mechanism of phenylcarbamate derivatives of cellulose. The structure of CTPC was optimized with the CHARMm force field based on the proposed structure of CTPC by X-ray analysis. In chromatographic enantioseparation on CTPC, 1 was completely resolved (alpha = 1.46) and the (R,R)-(+)-isomer eluted first followed by the (S,S)-(-)-isomer, but 2 was not resolved (alpha approximately 1). The results of calculation of interaction energies between CTPC and the enantiomers 1 suggested that the most important adsorbing site of CTPC for 1 may be the NH protons of the carbamate moieties at the 3-position of glucose units, and the (S,S)-(-)-isomer of 1 may interact more closely than the (R,R)-(+)-isomer with CTPC. In contrast, there was little difference in the minimum interaction energies between the enantiomers 2. These calculations agreed with the observed results for the chromatographic resolution on CTPC.
The acetylcholine hydrolyzing enzyme, acetylcholinesterase, primarily functions in nerve conduction, yet it appears in several guises, due to tissue-specific expression, alternative mRNA splicing and variable aggregation modes. The closely related enzyme, butyrylcholinesterase, most likely serves as a scavenger of toxins to protect acetylcholine binding proteins. One or both of the cholinesterases probably also plays a non-catalytic role(s) as a surface element on cells to direct intercellular interactions. The two enzymes are subject to inhibition by a wide variety of synthetic (e.g., organophosphorus and carbamate insecticides) and natural (e.g., glycoalkaloids) anticholinesterases that can compromise these functions. Butyrylcholinesterase may function, as well, to degrade several drugs of interest, notably aspirin, cocaine and cocaine-like local anesthetics. The widespread occurrence of butyrylcholinesterase mutants with modified activity further complicates this picture, in ways that are only now being dissected through the use of site-directed mutagenesis and heterologous expression of recombinant cholinesterases.