Rescoring of docking poses under Occam’s Razor: are there simpler solutions?

Ligand affinity prediction from docking simulations is usually performed by means of highly empirical and diverse protocols. These protocols often involve the re-scoring of poses generated by a force field (FF) based Hamiltonian to provide either estimated binding affinities—or alternatively, some empirical goodness score. Re-scoring is performed by so-called scoring functions—typically, a reweighted sum of FF terms augmented by additional terms (e.g., desolvation/entropic penalty, hydrophobicity, aromatic interactions etc.). Sometimes, the scoring function actually drives ligand positioning, but often it only operates on the best scoring poses ranked top by the initial ligand positioning tool. In either of these rather intricate scenarios, scoring functions are docking-specific models, and most require machine-learning-based calibration. Therefore, docking simulations are less straightforward when compared to “standard” molecular simulations in which the FF Hamiltonian defines the energy, and affinity emerges as an ensemble average property over pools of representative conformers (i.e., the trajectory). Paraphrasing on Occam’s Razor principle, additional model complexity is only acceptable if demonstrated to bring a significant improvement of prediction quality. In this work we therefore examined whether the complexity inherent to scoring functions is indeed justified. For this purpose we compared sampler for multiple protein–ligand entities, a general purpose conformation sampler based on the AMBER/GAFF FF, complemented with continuum solvation terms, with several state of the art docking tools that rely on calibrated scoring functions (Glide, Gold, Autodock-Vina) in terms of its ability to top-rank the actives from large and diverse ligand series associated with various proteins. There is no clear winner of this study, where each program performed well on most of the targets, but also failed with respect to at least one of them. Therefore, a well-parameterized force field with a simple, energy-based ligand ranking protocol appears to be an as effective docking protocol as intricate rescoring strategies based on scoring functions. A tool that can sample the conformational space of the free ligand, the bound ligand and the protein binding site using the same force field may avoid many of the approximations common to contemporary docking protocols and allow e.g., for docking into highly flexible active sites, when current scoring functions are not well suited to estimate receptor strain energies.     

A simple procedure for hydrodynamic injection in flow injection analysis applied to the atomic absorption spectrometry of chromium in steels

The proposed technique for hydrodynamic injection is based on commutation in a simple flow-injection system with only one peristaltic pump. Precise results (usually r.s.d. < 1%) are attained even when injected volumes are small (1–10 μl). Dead-volume effects are associated with the mechanical flexibility of the system and with diffusion; differences between effective sample size and the dimensions of the injection duct are emphasized, particularly for small volumes. The proposed technique is checked for a spectrophotometric model system and confirmed by the atomic absorption spectrometry of chromium in steels. With a sampling rate of 120 h^?1, the precision is better than 99% for chromium contents in the 0.0–30.0% (w/w) range. The results agree well with those obtained by i.c.p./a/e/s. and conventional a.a.s.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and Prins cyclizations: a switch in diastereoselectivity between Lewis and Brønsted acid catalysts

[reaction: see text] A novel diastereoselective approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 6a-e catalyzed by the Lewis acid methyl aluminum dichloride in refluxing chloroform affords trans piperidines 8a-e with diastereomeric ratios of up to 93:7. By contrast, Prins cyclization of 6a-e catalyzed by hydrochloric acid at low temperatures affords cis products 7a-e with diastereomeric ratios of up to 98:2.     

Al-isopropoxydiisobutylalane: a study of the effect of solvent on the rate and stereoselectivity of cyclic ketone reduction

The effect of solvent on the rate and stereoselectivity of cyclic ketone reduction by Al-isopropoxydiisobutylalane (DIBA(i)OPr) has been investigated. In dichloromethane, DIBA(i)OPr behaves as a bulky reducing agent, approaching the carbonyl group along an equatorial trajectory to produce the axial alcohol with >10:1 stereoselectivity. In sharp contrast, reduction in toluene gives the complementary outcome, affording the thermodynamically more stable isomer with >99:1 stereoselectivity.     

Investigations on Hydrolytic Activities from Stachybotrys microspora and Their Use as an Alternative in Yeast DNA Extraction

Stachybotrys microspora is a filamentous fungus characterized by the secretion of multiple hydrolytic activities (cellulolytic and non-cellulolytic enzymes). The production of these biocatalysts was studied under submerged culture using glucose, cellulose, and wheat bran as carbon sources. Endoglucanases, pectinases, xylanases, β-glucanases, chitinases, and proteases were induced on cellulose-based medium and repressed on glucose in both strains with higher amounts produced by the mutant. β-glucosidases were roughly equally produced by both strains under glucose and cellulose conditions. The yield of chitinases, β-glucanases, and proteases produced by Stachybotrys strains was as much higher than the commercialized lysing enzyme called “zymolyase,” currently used in yeast DNA extraction. In this context, we showed that S. microspora hydrolases can be successfully applied in the extraction of yeast DNA.     

Determination of molybdenum in steels by flow-injection spectrophometry

A flow-injection procedure is proposed for the determination of molybdenum in steels based on the thiocyanate method. Effects of iron(III), acidity, reagent concentration and interfering species were investigated by using flow-injection systems with the merging zones approach which reduced drastically the number of standard solutions to be prepared. Full details of system design are given. The procedure can be applied to several types of steel samples of industrial relevance. After dissolution of the steels in aqua regia, molybdenum can be determined in the range 0.10–4.00% (w/w) at a rate of up to 270 samples per hour with relative standard deviations less than 2%. The results agree with those obtained by atomic absorption spectrometry with the standard addition method and by plasma atomic emission spectrometry, and with certified values of standard reference samples.     

Stability indicating methods for the determination of some anti-fungal agents using densitometric and RP-HPLC methods

Two chromatographic methods were developed for the determination of some anti-fungal drugs in the presence of either their degradation products or cortisone derivatives. The densitometric method determined mixtures of each of ketoconazole (KT), clotrimazole (CL), miconazole nitrate (MN) and econazole nitrate (EN) with the degradation products of each one. Mixtures of MN with hydrocortisone (HC) and of EN with triamcinolone acetonide (TA) were also successfully separated and determined by this technique. For KT and CL, a mixture of methanol:water:triethylamine (70:28:2 v/v) was used as a developing system and the spots were scanned at 243 nm and 220 nm for KT and CL, respectively. For MN and EN, a mixture of hexane:isopropyl alcohol:triethylamine (80:17:3 v/v) was used as a developing system and the spots were scanned at 225 nm for both drugs. The HPLC method determined mixtures of CL or EN with their degradation products which were separated and quantified on a Zorbax C8 column. Elution was carried out using methanol:phosphate buffer pH 2.5 (65:35 v/v) as a mobile phase at a flow rate of 1.5 ml/min and UV detection at 220 nm for CL. For EN, a mixture of methanol:water containing 0.06 ml triethylamine pH 10 (75:25 v/v) was used as a mobile phase at a flow rate of 1.5 ml/min and UV detection at 225 nm. The methods were also used to separate mixtures of CL with betamethasone dipropionate (BD) and EN with TA in a laboratory prepared mixture and in pharmaceutical preparations. The methods were sensitive, precise and applicable for determination of the drugs in pharmaceutical dosage forms.     

A study of some parameters relevant to the response of harwell PMMA dosimeters to gamma and electron irradiation

The effects on the radiation response of Harwell polymethylmethacrylate (PMMA) dosimeters of dose-rate, radiation type, temperature during irradiation and post-irradiation storage, and post-irradiation stability, are of importance to the operators of commercial irradiation facilities.

This paper describes recent studies of the effects of some of these parameters on the radiation response of Harwell Red 4034, Amber 3042, and Gammachrome YR Perspex dosimeters, and provides data on batch to batch variation and shelf-life.     

Combination of Statistical Similarity Measure and Derivative Morphological Profile Approach for Oil Slick Detection in SAR Images

Synthetic Aperture Radar (SAR) is widely used to detect and monitor oil pollution on the sea surface. As it is sensitive to surface roughness, the presence of oil film on the sea surface decreases the backscattering of this target type resulting in a dark feature patches in SAR images. In this paper, a new approach for oil slicks detection is presented. It is mainly based on SAR image texture analysis using the combination of a statistical similarity measure and a derivative morphological profile. Oil slicks signature is extracted trough two steps procedure. First, SAR image inspection is performed in order to highlight the dark spots suspected to be oil slicks. The inspection is achieved through a similarity measure between a local probability density function (lpdf) of clean water and the lpdf of the area to be inspected. The local distribution is estimated in the neighbourhood of each pixel and compared to a reference one using the Kullback-Leibler KL distance between distributions. Second, and once spots highlighted, texture features extraction using the Derivative Morphological Profile is porformed in order to improve the detection results. algorithm has been applied to Envisat Advanced Synthetic Aperture Radar (ASAR) and European Remote Sensing (ERS) images and it yields an accurate segmentation results. Indeed, the features extraction improves the detection slicks probability Pd of ASAR, respectively ERS, images from 93.08 %to 97.37 %and from 96.32 to 99.57 % on one hand, and reduces the false alarms probability respectively from 6.92 to 2.63 %and from 3.68 to 0.59 % on the other hand.