Random sampling or 'random' model in skin flux measurements? [Commentary on "Investigation of the mechanism of flux across human skin in vitro by quantitative structure-permeability relationships"].

Transdermal therapy receives increasing attention as an attractive alternative to traditional drug delivery. Unfortunately the exact algorithm of transdermal permeation that could guide medicinal chemists towards delivery optimization at an early stage of the drug design process still remains to be decoded. This paper discusses some major hurdles on the way to full understanding of Quantitative Structure-Activity Relationships (QSAR) of skin permeation. From the statistical perspective, a recently published combined data set is found to be inappropriate with respect to the distribution of major molecular descriptors, and therefore should be approached cautiously as a source for QSAR model training and in modelling of occupational and environmental skin exposures.

Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study.

A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.

[Evolutionary programming for finding "structure-activity" relationships in a series of 3-phenoxychromone and 3-phenoxy-4-hydroxycoumarin derivatives]. / Evoliutsionnoe programmirovanie dlia vyiavleniia zakonomernostei "struktura-aktivnost" v riadu proizvodnykh 3-fenoksikhromona i 3-fenoksi-4-gidroksikumarina.

Based on a set of compounds possessing hypolipidemic activity, it was demonstrated that evolutionary algorithms can be successfully used to compile an informative set of molecular parameters. The parameter sets selected using the method of potential functions allowed correct prediction of the activity of test molecules.

HIV-1 reverse transcriptase inhibitor design using artificial neural networks.

Artificial neural networks were used to analyze and predict the human immunodeficiency virus type 1 reverse transcriptase inhibitors. The training and control sets included 44 molecules (most of them are well-known substances such as AZT, dde, etc.). The activities of the molecules were taken from literature. Topological indices were calculated and used as molecular parameters. The four most informative parameters were chosen and applied to predict activities of both new and control molecules. We used a network pruning algorithm and network ensembles to obtain the final classifier. Increasing of neural network generalization of the new data was observed, when using the aforementioned methods. The prognosis of new molecules revealed one molecule as possibly very active. It was confirmed by further biological tests.

Similarity of the effects of tosyl-L-arginine methyl ester, atropine, caffeine and antitumour alkylating agent on some biological functions of thrombin and platelet 12-lipoxygenase.

The effect of the synthetic thrombin substrate (TAME) and three compounds exerting an opposite effect on Ca-PPI and AdC (caffeine, atropine and meta-tolyl derivative of mechlorethamine (TDM)) on hormone-like and catalytic functions of thrombin was studied. It is shown that both TAME and other drugs under test block effectively the thrombin-induced platelet aggregation, as well as protect the active site of the enzyme from denaturation by dithiothreitol. The same compounds inhibit thrombin in thrombin-fibrinogen reaction and platelet 12-lipoxygenase. These data suggest identity of thrombin moieties which determine its enzymatic and hormone-like activities.

Applications of neural networks in structure-activity relationships of a small number of molecules.

We investigated the applications of back propagation artificial neural networks (ANN) for a small dataset analysis in the field of structure-activity relationships. The derivatives of carboquinone were used as an example. It's been found that in this case the use of the same neural network results in unambiguous classification of new molecules. Predictions can be improved with statistical analysis of independent prognosis sets. We suggest that the sign criterion be used as a classification rule. We also compared neural networks with FALS and ALS in leave-one-out prediction. ANN applied to the same dataset has shown the same predictive ability as ALS but poorer than FALS.

[Membrane mechanisms of the effect of alkylating cytostatic agents]. / Membrannye mekhanizmy deistviia alkiliruiushchikh tsitostatikov.

The data bearing witness to realization of the cytostatic activity of alkylating agents by means of interaction with cell membrane receptors was obtained. Alkylating agents block receptors of the polyphosphoinositol system. It is shown that chloralkylamines inhibiting sites coincide with M-++cholinomimetics and alpha-adrenergic receptors, inhibitors of H-histamine receptors, cyclo- and lypoxigenase inhibitors. Such likeness is determined by identical structures of the molecule active part, and quantum-chemical calculations.

[Soy lipoxygenase as the object for the primary testing of potential inhibitors of leukotriene biosynthesis]. / Soevaia lipoksigenaza kak ob''ekt pervichnogo testirovaniia potentsialnykh ingibitorov biosinteza leikotrienov.

The comparative study of the ability of three compounds (indomethacin, agent BW 755 C and arachidonate hydroxamic acid) to inhibit the activity of preparations of soya bean lipoxygenase and to block leukotriene C4 biosynthesis in human leukocytes recorded by reversed phase liquid chromatography was performed. It was shown that irrespectively of purification degree soya bean lipoxygenase is a sufficiently adequate object for primary testing of inhibitors of biosynthesis of leukotrienes with the given type of action. Compounds with IC50 less than or equal to 1.10(-6) mol/l might be considered promising for the further investigation.