Genetic algorithms applied to the selection of factors in principal component regression

Using principal component regression (PCR) as a multivariate calibration tool, always brings up the question what subset of factors, i.e. principal components (PCs) gives the best calibration model. Normally factor selection is based on deterministic methods like top–down procedures, forward–backward-stepwise variable selection or correlated principal component regression (CPCR). In contrast to this, we applied a stochastic method, i.e. a genetic algorithm (GA) for factor selection in this paper. A new kind of fitness function was applied which combined the prediction error of the calibration and an independent validation set. The performance of eigenvalue and correlation ranking was compared. A general statistical criterion for judging the significance of differences between individual calibration models is introduced. In this context it could be shown that for the uncertainties of the standard deviations representing the prediction errors a very simple approximation formula holds which only includes the number of standards. For the current applications it is shown that the GA gives a result very close to CPCR-solutions.     

Synthesis and binding properties of 2H-1-benzopyran-2 one fluorophore-linked calcium channel antagonist nifedipine (1,4-dihydropyridine) analogs

Nifedipine analogs I, II and III with the 2H-1-benzopyran-2-one (coumarin) fluorophore linked at the 2, 2 and 6 and 4 positions of the dihydropyridine ring were synthesized by the modified Hantzch condensation procedures. Attempts to synthesize dihydropyridine with the fluorophore at position 3 (IV) were unsuccessful.     

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-di-hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of an excess amount of NH₄OAc. Also, the reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of enamino esters and ketones was performed, and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines were obtained in moderate to good yields at room temperature. The calcium channel blocking activity of these compounds was assessed. They demonstrated moderate to weak effects, although one compound had a comparable effect (IC₅₀ =1.40×10⁻⁷ M) with respect to the reference drug Nifedipine.     

A mononuclear complex of copper(II) with a calcium channel antagonist nifedipine. Synthesis,properties, crystal structure

The complexation processes between the calcium channel antagonist drug nifedipine (Nif) and Cu^II lead to the formation of a mononuclear violet complex CuNif₂Cl₂ (1). Monocrystals of (1) were isolated and their structure determined by X-ray diffraction. Copper is coordinated through N of the NH group of the ligand. The metal ion is coordinated also with two Cl^– anions and the geometry of the CuN₂Cl₂ core is a near flat square. The magnetic and optical properties of (1) were also studied using electronic and i.r. spectra, e.p.r. and magnetochemical measurements.     

GA strategy for variable selection in QSAR studies: application of GA-based region selection to a 3D-QSAR study of acetylcholinesterase inhibitors

Comparative molecular field analysis (CoMFA) with partial least squares (PLS) is one of the most frequently used tools in three-dimensional quantitative structure-activity relationships (3D-QSAR) studies. Although many successful CoMFA applications have proved the value of this approach, there are some problems in its proper application. Especially, the inability of PLS to handle the low signal-to-noise ratio (sample-to-variable ratio) has attracted much attention from QSAR researchers as an exciting research target, and several variable selection methods have been proposed. More recently, we have developed a novel variable selection method for CoMFA modeling (GARGS: genetic algorithm-based region selection), and its utility has been demonstrated in the previous paper (Kimura, T., et al. J. Chem. Inf. Comput. Sci. 1998, 38, 276-282). The purpose of this study is to evaluate whether GARGS can pinpoint known molecular interactions in 3D space. We have used a published set of acetylcholinesterase (AChE) inhibitors as a test example. By applying GARGS to a data set of AChE inhibitors, several improved models with high internal prediction and low number of field variables were obtained. External validation was performed to select a final model among them. The coefficient contour maps of the final GARGS model were compared with the properties of the active site in AChE and the consistency between them was evaluated.     

Synthesis and calcium channel antagonist activities of new derivatives of dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates

The new analogues of nifedipine, in which 2-nitrophenyl group at position 4 is replaced by phenylisoxazolyl substituent, were synthesized. The symmetrical dialkyl 1,4-dihydro-2,6-dimethyl-4-(5-phenylisoxazol-3-yl)pyridine-3,5-dicarboxylates were prepared by classical Hantzsch condensation, and the asymmetrical analogues were synthesized using a procedure reported by Dagnino that involved the condensation of alkyl acetoacetate with alkyl 3-aminocrotonate and 5-phenylisoxazole-3-carboxaldehyde. The structure of all compounds was confirmed by IR, ¹H NMR and Mass spectra. In vitro calcium channel antagonist activities were evaluated as calcium channel antagonists using the high K⁺ concentration of guinea-pig ileum longitudinal smooth muscle (GPILSM) assay. These compounds exhibited moderate calcium antagonist activity (IC₅₀ = 10^?7 to 10^{? 5} M range) relative to the reference drug nifedipine (IC₅₀ = 1.10 ± 0.40 × 10^?8 M).     

A new protocol to synthesize 1,4-dihydropyridines by using 3,4,5-trifluorobenzeneboronic acid as a catalyst in ionic liquid: synthesis of novel 4-(3-carboxyl-1H-pyrazol-4-yl)-1,4-dihydropyridines

3,4,5-Trifluorobenzeneboronic acid catalysed, ionic liquid mediated facile synthesis of 4-pyrazolyl 1,4-dihydropyridines at room temperature by the cyclocondensation of ethyl 3-aminocrotonate, pyrazole aldehyde and a β-keto ester is reported. The procedure adopted was found to be eco-benign, facile at room temperature and better than the conventional, [bmim]Cl mediated and InCl₃ catalysed, [bmim]Cl mediated 1,4-dihydropyridine syntheses.     

The non-grid technique for modeling 3D QSAR using self-organizing neural network (SOM) and PLS analysis: application to steroids and colchicinoids

A novel method for modeling 3D QSAR has been developed. The method involves a multiple training of a series of self-organizing networks (SOM). The obtained networks have been used for processing the data of one reference molecule. A scheme for the analysis of such data with the PLS analysis has been proposed and tested using the steroids data with corticosteroid binding globulin (CBG) affinity. The predictivity of the CBG models measured with the SDEP parameter is among the best one reported. Although 3-D QSAR models for colchicinoid series is far less predictive, it allows for a discussion on the relative influence of the structural motifs of these compounds.     

Artificial neural networks study of the catalytic reduction of resazurin: stopped-flow injection kinetic-spectrophotometric determination of Cu(II) and Ni(II)

An artificial neural network (ANN) procedure was used in the development of a catalytic spectrophotometric method for the determination of Cu(II) and Ni(II) employing a stopped-flow injection system. The method is based on the catalytic action of these ions on the reduction of resazurin by sulfide. ANNs trained by back-propagation of errors allowed us to model the systems in a concentration range of 0.5-6 and 1-15 mg l⁻¹ for Cu(II) and Ni(II), respectively, with a low relative error of prediction (REP) for each cation: REP_Cu(II) = 0.85% and REP_Ni(II) = 0.79%. The standard deviations of the repeatability (s_r) and of the within-laboratory reproducibility (s_w) were measured using standard solutions of Cu(II) and Ni(II) equal to 2.75 and 3.5 mg l⁻¹, respectively: s_r[Cu(II)] = 0.039 mg l⁻¹, s_r[Ni(II)] = 0.044 mg l⁻¹, s_w[Ni(II)] = 0.045 mg l⁻¹ and s_w[Ni(II)] = 0.050 mg l⁻¹. The ANNs-kinetic method has been applied to the determination of Cu(II) and Ni(II) in electroplating solutions and provided satisfactory results as compared with flame atomic absorption spectrophotometry method. The effect of resazurin, NaOH and Na₂S concentrations and the reaction temperature on the analytical sensitivity is discussed.     

On the construction of 2-substituted 1,4-diacetoxybutadiene moiety: application to the synthesis of (±)-caulerpenyne

The synthesis of 2-substituted 1,4-diacetoxybutadiene derivatives with a partial control of stereochemistry is described from two potentially precursor enals by a judicious choice of experimental conditions (Ac₂O/DMAP in Et₃N). These conditions have been successfully applied in the first total synthesis of caulerpenyne.     

Three-dimensional quantitative structure activity relationship (QSAR) of cytotoxic active 3,5-diaryl-4,5-dihydropyrazole analogs: a comparative molecular field analysis (CoMFA) revisited study

ABSTRACT: In vitro antitumor evaluation of the synthesized 46 compounds of 3,5-diaryl-4,5-dihydropyrazoles against EAC cell lines and 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2 cv 0.896 and 0.568 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 70% and 30% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals) interactions. To visualize the CoMFA steric and electrostatic field from partial least squares (PLS) analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity. BACKGROUND: Pyrazole derivatives exhibit a wide range of biological properties including promising antitumor activity. Furthermore, Aldol condensation assisted organic synthesis has delivered rapid routes to N-containing heterocycles, including pyrazoles. Combining these features, the use of chalconisation-assisted processes will provide rapid access to a targeted dihydropyrazoles library bearing a hydrazino 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described for evaluation of antioxidant properties. RESULTS: Chalcones promoted 1 of the 2 steps in a rapid, convergent synthesis of a small library of hydrazinyl pyrazole derivatives, all of which exhibited significant antitumor activity against Ehrlich Ascites Carcinoma (EAC) human tumor cell line comparable to that of the natural anticancer doxorubicin, as a reference standard during this study. In order to understand the observed pharmacological properties, quantitative structure-activity relationship (3D QSAR) study was initiated. CONCLUSIONS: Chalcones heating provides a rapid and expedient route to a series of pyrazoles to investigate their chracterization scavenging properties. Given their favorable properties, in comparison with known anticancer, these pyrazole derivatives are promising leads for further development and optimization.     

(De)constructing the ryanodine receptor: modeling ion permeation and selectivity of the calcium release channel

Biological ion channels are proteins that passively conduct ions across membranes that are otherwise impermeable to ions. Here, we present a model of ion permeation and selectivity through a single, open ryanodine receptor (RyR) ion channel. Combining recent mutation data with electrodiffusion of finite-sized ions, the model reproduces the current/voltage curves of cardiac RyR (RyR2) in KCl, LiCl, NaCl, RbCl, CsCl, CaCl(2), MgCl(2), and their mixtures over large concentrations and applied voltage ranges. It also reproduces the reduced K(+) conductances and Ca(2+) selectivity of two skeletal muscle RyR (RyR1) mutants (D4899N and E4900Q). The model suggests that the selectivity filter of RyR contains the negatively charged residue D4899 that dominates the permeation and selectivity properties and gives RyR a DDDD locus similar to the EEEE locus of the L-type calcium channel. In contrast to previously applied barrier models, the current model describes RyR as a multi-ion channel with approximately three monovalent cations in the selectivity filter at all times. Reasons for the contradicting occupancy predictions are discussed. In addition, the model predicted an anomalous mole fraction effect for Na(+)/Cs(+) mixtures, which was later verified by experiment. Combining these results, the binding selectivity of RyR appears to be driven by the same charge/space competition mechanism of other highly charged channels.