Fuzzy virtual ligands for virtual screening

A new method to bridge the gap between ligand and receptor-based methods in virtual screening (VS) is presented. We introduce a structure-derived virtual ligand (VL) model as an extension to a previously published pseudo-ligand technique [1]: LIQUID [2] fuzzy pharmacophore virtual screening is combined with grid-based protein binding site predictions of PocketPicker [3]. This approach might help reduce bias introduced by manual selection of binding site residues and introduces pocket shape information to the VL. It allows for a combination of several protein structure models into a single "fuzzy" VL representation, which can be used to scan screening compound collections for ligand structures with a similar potential pharmacophore. PocketPicker employs an elaborate grid-based scanning procedure to determine buried cavities and depressions on the protein's surface. Potential binding sites are represented by clusters of grid probes characterizing the shape and accessibility of a cavity. A rule-based system is then applied to project reverse pharmacophore types onto the grid probes of a selected pocket. The pocket pharmacophore types are assigned depending on the properties and geometry of the protein residues surrounding the pocket with regard to their relative position towards the grid probes. LIQUID is used to cluster representative pocket probes by their pharmacophore types describing a fuzzy VL model. The VL is encoded in a correlation vector, which can then be compared to a database of pre-calculated ligand models. A retrospective screening using the fuzzy VL and several protein structures was evaluated by ten fold cross-validation with ROC-AUC and BEDROC metrics, obtaining a significant enrichment of actives. Future work will be devoted to prospective screening using a novel protein target of Helicobacter pylori and compounds from commercial providers

Development of a pseudoreceptor model for virtual screening

Im Rahmen dieser Arbeit wurde die Eignung von Pseudorezeptoren im virtuellen Screening untersucht. Hierzu wurde nach intensiver Auseinandersetzung mit bisher bekannten Konzepten ein neues Computerprogramm zur automatischen Konstruktion von Pseudorezeptormodellen entwickelt. Das Ziel von Pseudorezeptoren ist die Konstruktion eines alternativen, artifiziellen Wirtssystems aus bekannten Liganden eines Zielproteins, dessen dreidimensionale Struktur unbekannt ist. Der generierte Pseudorezeptor ist zu verstehen als die Menge aller Pseudoatome, die um die Ausgangssubstanz(en) projiziert werden. Bei multiplen Referenzliganden wird eine Gewichtung der Pseudoatome durchgeführt. Zudem wird ausschließlich von Distanz- und Winkelparametern Gebrauch gemacht, die aus Untersuchungen von Kokristall-strukturen gewonnenen wurden. Eine abschließende Kodierung generierter Pseudorezeptoren als 90-dimensionalen Korrelationsvektor wurde zum virtuellen Screening eingesetzt. In zwei retrospektiven Fallbeispielen wird gezeigt, dass die generierten Pseudorezeptoren für COX-2 und PPARα mit den realen Zuständen ihrer kokristallisierten Bindetaschen in den PDB Einträge 6cox und 2p54 kompatibel sind. Im retrospektiven virtuellen Screening in der Wirkstoffdatenbank COBRA (8.311 Moleküle) nach COX-2 Inhibitoren (136 Aktive) konnte eine Anreicherung der aktiven Strukturen in den ersten zwei Perzentilen gezeigt werden (54% der Aktiven). Zudem konnten 80% der aktiven Moleküle bereits nach Vorhersage von 10% Falsch-Positiven gefunden werden. Im Falle des retrospektiven Screenings nach 94 PPAR Liganden konnten 30% der aktiven Moleküle nach der Vorhersage von 10% Falsch-Positiven entdeckt. Nach 20% Falsch-Positiver wurden 46% der PPAR Liganden wieder gefunden. Weiterhin konnte mit den ligandenbasierten Informationen eines H4 Pseudorezeptors eine Justierung einer potentiellen Bindetasche des Histamin H4 Rezeptors aus einer molekularen Dynamiksimulation vorgenommen werden. Schließlich wurde in einem prospektiven virtuellen Screening nach Histamin H4 Liganden mit einem Pseudorezeptor zwei Strukturen mit unterschiedlichem Grundgerüst und einem Ki ~ 30 µM identifiziert.In this thesis, the suitability of pseudoreceptors for virtual screening applications was analyzed. An automated pseudoreceptor construction program was developed after known design principles had been thoroughly studied and compared. The aim of pseudoreceptor modelling is the construction of an alternative host system for known ligands of a given target protein in the absence of three-dimensional structure information. The constructed pseudoreceptor is represented as the sum of all pseudoatoms, which are projected around reference ligand(s). A weighting scheme is introduced, when pseudoreceptors are generated from multiple reference ligands. For pseudoatom placing distance and angle parameters from a survey of known co-crystal structures were used. For virtual screening pseudoreceptors were encoded as correlation vectors. It is demonstrated that the generated pseudoreceptors match with their respective co- crystallized binding pockets, taking COX-2 and PPAR-alpha as an example (PDB entries 6cox and 2p54). In a retrospective virtual screening in the drug collection COBRA (8,311 molecules) for COX-2 inhibitors (136 actives) high enrichment of ligands in the first two percentiles was yielded (54% of the actives). 80% of all active compounds were found after the prediction of only 10% false-positives. In a retrospective screening study for 94 PPAR ligands, 30% of the actives were found together with 10% false-positives. After the prediction of 20% false-positives, 46% of all PPAR ligands could be found. In addition, a putative binding pocket of the histamine H4 receptor from a molecular dynamics simulation could be adjusted using ligand-based information of a H4 pseudoreceptor. Finally, two micromolar ligands with different scaffolds were identified with a Ki ~ 30 µM by a pseudoreceptor-based prospective virtual screening for novel H4 ligands

Pseudoreceptor-based pocket selection in a molecular dynamics simulation of the histamine H4 receptor

There is a renewed interest in pseudoreceptor models which enable computational chemists to bridge the gap of ligand- and receptor-based drug design. We developed a pseudoreceptor model for the histamine H4 receptor (H4R) based on five potent antagonists representing different chemotypes. Here we present the selection of potential ligand binding pockets that occur during molecular dynamics (MD) simulations of a homology-based receptor model. We present a method for prioritizing receptor models according to their match with the consensus ligand-binding mode represented by the pseudoreceptor. In this way, ligand information can be transferred to receptor-based modelling. We use Geometric Hashing to match three-dimensional points in Cartesion space. This allows for the rapid translation- and rotation-free comparison of atom coordinates, which also permits partial matching. The only prerequisite is a hash table, which uses distance triplets as hash keys. Each time a distance triplet occurring in the candidate point set which corresponds to an existing key, the match is represented by a vote of the respective key. Finally, the global match of both point sets can be easily extracted by selection of voted distance triplets. The results revealed a preferred ligand-binding pocket in H4R, which would not have been identified using an unrefined homology model of the protein. The key idea was to rely on ligand information by pseudoreceptor modelling

Atomic-layer-deposited zinc oxide as tunable uncooled infrared microbolometer material

ZnO is an attractive material for both electrical and optical applications due to its wide bandgap of 3.37eV and tunable electrical properties. Here, we investigate the application potential of atomic-layer-deposited ZnO in uncooled microbolometers. The temperature coefficient of resistance is observed to be as high as -10.4%K-1 near room temperature with the ZnO thin film grown at 120 degrees C. Spectral noise characteristics of thin films grown at various temperatures are also investigated and show that the 120 degrees C grown ZnO has a corner frequency of 2kHz. With its high TCR value and low electrical noise, atomic-layer-deposited (ALD) ZnO at 120 degrees C is shown to possess a great potential to be used as the active layer of uncooled microbolometers. The optical properties of the ALD-grown ZnO films in the infrared region are demonstrated to be tunable with growth temperature from near transparent to a strong absorber. We also show that ALD-grown ZnO can outperform commercially standard absorber materials and appears promising as a new structural material for microbolometer-based applications

SQUIRRELnovo : de novo design of a PPARalpha agonist by bioisosteric replacement

Shape complementarity is a compulsory condition for molecular recognition. In our 3D ligand-based virtual screening approach called SQUIRREL, we combine shape-based rigid body alignment with fuzzy pharmacophore scoring. Retrospective validation studies demonstrate the superiority of methods which combine both shape and pharmacophore information on the family of peroxisome proliferator-activated receptors (PPARs). We demonstrate the real-life applicability of SQUIRREL by a prospective virtual screening study, where a potent PPARalpha agonist with an EC50 of 44 nM and 100-fold selectivity against PPARgamma has been identified..

Accidental swallowing of partial denture: a case report

We describe a 42-year-old age woman who accidentally swallowed her lower denture, which was composed of eleven teeth. The daily descent of the denture was followed by plain abdominal radiography and physical examination. The image was localized at the left upper quadrant on admission day, but it stopped on its way at the right lower quadrant on day two and three. Since the patient's complaints increased we planned surgical removal of the denture. In this report, we had discussed the diagnosis, follow up and treatment options of swallowed partial denture with current literature review

IMPORTANCE OF SEVERITY SCORES: OUR RESULTS IN FIFTY-TWO PATIENTS

WOS: 000363826100029Background: Fournier's gangrene (FG) is a rare, an acute, rapidly progressive, fatal necrotizing fasciitis of the genital, perianal and perineal areas. The incidence of mortality is still high, and mortality increases with age. In this study we purposed our experience in the treatment of FG and to determine risk factors affecting prognosis. Methods: Fifty-two patients operated for FG who presented at our hospital from January 2009 to December 2014 were investigated retrospectively. Patients were divided into two groups; surviving and non-surviving. Groups were compared regarding demographic features, vital signs and laboratory analysis, PG severity scores and surgical treatment requirements. Results: Mean age was 56.4 years, and female/male ratio was 20/32. The mortality rate was 9.6% (5 patients), and significantly higher in men (80%). The two most common etiological factors were soft tissue infection (63.5%) and anorectal diseases (28.8%). There was difference between groups in terms of requirements fecal diversion, respiratory rate, potassium and urea levels (p<0.05). There was significant difference between groups according to the FG severity index (FGSI) and illudag FGSI (respectively p=0.001 and p=0.002). There were no significant difference between groups according to the duration of symptoms and hospitalization, use of antibiotic, etiology, wound culture and debridement number. Conclusions: FG is an unpredictable fulminant disease and there is need for new proposals to reduce morbidity and mortality. In our study, male gender, hypokalemia, uremia and increased respiratory rate at first presentation, and having a neurological disease were found to be the factors affecting mortality in FG patients

A Detailed Analysis for the Absorption Coefficient of Multilevel Uncooled Infrared Detectors

This paper introduces a detailed analysis on the calculation of the absorption coefficient of multilevel uncooled infrared detectors. The analysis is carried out considering a two-level 25 mu m pixel pitch infrared detector with a sandwich type resistor which is divided into sub-regions consisting of different stacks of layers. The absorption coefficients of these different sub-regions are calculated individually by using the cascaded transmission line model, including the main body, arms, and the regions where the resistors are implemented. Then, the total absorption coefficient of the detector is found by calculating the weighted average of these individual absorption coefficients, where the areas of sub-regions are taken into account. The absorption can be calculated as a function of the sacrificial and structural layer thicknesses together with the sheet resistance of the absorber layer to find the optimum value. However, the thermal conductance of the detector must be considered while adjusting the structural layer thickness. The proposed analysis also takes the thermal conductance into account in order not to compromise the overall detector performance. Analysis shows that a maximum absorption coefficient of 0.92 for a specific two-level pixel can be obtained at the 10 mu m wavelength, while the pixel results in a time constant of 11.3 ms with 27.2 nW/K thermal conductance in the thermal simulation. It is shown that the absorption coefficient of the pixel is maximized when the sheet resistance of the absorber is 380 Omega/square, which is almost equal to the free space impedance, as expected

A low-cost 128x128 uncooled infrared detector array in CMOS process

This paper discusses the implementation of a low-cost 128 x 128 uncooled infrared microbolometer detector array together with its integrated readout circuit (ROC) using a standard 0.35 mu m n-well CMOS and post-CMOS MEMS processes. The detector array can be created with simple bulk-micromachining processes after the CMOS fabrication, without the need for any complicated lithography or deposition steps. The array detectors are based on suspended p(+)-active/n-well diode microbolometers with a pixel size of 40 mu m x 40 mu m and a fill factor of 44%. The p(+)-active/n-well diode detector has a measured dc responsivity (R) of 4970 V/W and a thermal time constant of 36 ms at 50 mtorr vacuum level. The total measured rms noise of the diode type detector is 0.69 mu V for an 8 kHz bandwidth, resulting in a detectivity (D*) of 9.7 x 10(8) cm . Hz(1/2)/W. The array is scanned by an integrated 32-channel parallel ROC including low-noise differential preamplifiers with an electrical bandwidth of 8 kHz. The 128 x 128 focal plane array (FPA) has one row of infrared-blind reference detectors that reduces the effect of FPA fixed pattern noise and variations in the operating temperature relaxing the requirements for the temperature stabilization. Including the noise of the reference and array detectors together with the ROC noise, the fabricated 128 x 128 FPA has an expected noise equivalent temperature difference (NETD) value of 1 K for f/1 optics at 30 frames/s (fps) scanning rate. This NETD value can be decreased to 350 mK by improving the post-CMOS fabrication steps and increasing the number of readout channels

A new method to estimate the absorption coefficient for uncooled infrared detectors

his paper introduces a new method to estimate the total absorption coefficient of uncooled infrared detectors. Current approaches in the literature model the infrared detectors as cascaded transmission lines representing the detector layers, and this model can easily be used to estimate the absorption coefficient if the detector has the same structure at every point. However, the state of the art uncooled infrared detectors do not have same structure at every point, making it not feasible to use this simple model. According to the proposed method, the detector structure is divided into subregions having different layer combinations, and the absorption coefficient of each subregion is calculated separately. Then, the area ratios of the subregions together with these coefficients are used in order to calculate the total absorption coefficient of the detector. As the estimation of the absorption coefficient for complex detector structures can easily be done, the absorption in the required part of the infrared spectrum can be optimized by adjusting the layer properties and layer thicknesses. This approach can be used both for single and double layer uncooled infrared detector structures