Search

The inhibition of kinases has been pursued by the pharmaceutical industry for over 20 years. While the locations of the sites that bind type II and III inhibitors at or near the adenosine 5'-triphosphate binding sites are well defined, the literature describes 10 different regions that were reported as regulatory hot spots in some kinases and thus are potential target sites for type IV inhibitors. Kinase Atlas is a systematic collection of binding hot spots located at the above ten sites in 4910 structures of 376 distinct kinases available in the Protein Data Bank. The hot spots are identified by FTMap, a computational analogue of experimental fragment screening. Users of Kinase Atlas ( https://kinase-atlas.bu.edu ) may view summarized results for all structures of a particular kinase, such as which binding sites are present and how druggable they are, or they may view hot spot information for a particular kinase structure of interest.

We present a case of bilateral choroidal abscesses due to a multidrug-resistant gram negative (4MRGN) Pseudomonas aeruginosa lung colonization in a patient with cystic fibrosis under immunosuppression after lung transplantation. Bilateral choroidal and subretinal abscesses were detected by funduscopy, ultrasound, magnetic resonance imaging (MRI) and phacovitrectomy and were accompanied by bilateral acute vision loss. The diagnosis was confirmed by intraoperative subretinal biopsy. Due to therapy resistance a bilateral enucleation for life-saving purposes was performed.

The key objectives of medicinal chemistry are to efficiently design and synthesize bioactive compounds that have the potential to become safe and efficacious drugs. Most medicinal chemistry programmes rely on screening compound collections populated by a range of molecules derived from a set of known and robust chemistry reactions. Analysis of the role of synthetic organic chemistry in subsequent hit and lead optimization efforts suggests that only a few reactions dominate. Thus, the uptake of new synthetic methodologies in drug discovery is limited. Starting from the known limitations of reaction parameters, synthesis design tools, synthetic strategies and innovative chemistries, here we highlight opportunities for the expansion of the medicinal chemists' synthetic toolbox. More intense crosstalk between synthetic and medicinal chemists in industry and academia should enable enhanced impact of new methodologies in future drug discovery.

Das Ektropium ist neben dem Entropium die haufigste Unterlidfehlstellung. Um bei der chirurgischen Korrektur ein moglichst nachhaltiges Ergebnis zu erzielen, mussen verschiedene pathogenetische Faktoren wie die Lidbandstabilitat, die vertikale Hautstrecke, entzundliche, traktive oder paralytische Ursachen berucksichtigt werden. Es erfolgen die Darstellung der pathogenetischen Faktoren und deren chirurgische Korrekturmoglichkeiten sowie die Auswertung der Literatur zur Identifikation und Beurteilung der wichtigsten Gesichtspunkte einer nachhaltigen Ektropiumtherapie. Senile Erschlaffung der Lidbander, narbige Traktion an der Lidkante, eine Fazialisparese und/oder eine Verkurzung der anterioren Lidlamelle sind die wichtigsten pathogenetischen Faktoren eines Ektropiums. Zur operativen Korrektur stehen verschiedene Formen der Kanthopexie oder Kanthoplastik zur Verfugung. Diese sollten z. B. bei paralytischem Ektropium mit einer Mittelgesichtsanhebung oder bei einem vertikalen Hautdefizit mit einer Hauttransplantation kombiniert werden. Berucksichtigt man insgesamt alle pathogenetisch relevanten Faktoren beim Ektropium und wahlt die chirurgisch passende Methode, ist eine erfolgreiche und auch nachhaltige Korrektur des Ektropiums zu erzielen.

Oculoplastic surgery places special demands on postoperative care because of the functional importance of the eyelids for the ocular surface. We present an overview of postoperative care after surgical eyelid interventions. All options, limits and the scientific evidence are discussed with a special focus on the treatment of postoperative edema, analgesia, infection prophylaxis and scar treatment.

Es stellte sich eine elfjahrige Patientin mit lamellarer Ichthyose vor, die unter einer schweren infektiosen Keratitis, bedingt durch ein Ektropium, litt. Die lamellare Ichthyose ist eine autosomal-rezessiv vererbte Erkrankung, welche mit Hyperkeratosen, schmerzhaften Fissuren und einem fehlreguliertem Vitamin-D Haushalt vergesellschaftet ist. Auf Grund der fortgeschrittenen Hornhautinfiltrate trotz einer maximalen topischen antibiotischen Therapie entschlossen wir uns zur Durchfuhrung eines Crosslinkings bei Keratitis (PACK-CXL-photoactivated corneal crosslinking for keratitis). Es zeigten sich ein Ruckgang der Hornhautinfiltrate, sowie eine Ausdunnung der Hornhaut. PACK-CXL kann eine Keratoplastik a chaud bei therapierefraktarer Keratitis vermeiden.

Hintergrund Basalzellkarzinome (BCC) zahlen zu den haufigsten periorbitalen Tumoren. Der Goldstandard der Behandlung ist eine histologisch gesicherte R0-Resektion des Tumors mit anschliesender Rekonstruktion der periorbitalen Region. Bei weit fortgeschrittenen Befunden oder inoperablen Patienten sind alternative Therapiestrategien erforderlich. Seit der Zulassung von Vismodegib steht auch eine orale Therapie zur Behandlung des BCC zur Verfugung. Fur den Einsatz bei periorbitalen BCC stehen jedoch noch wenige Daten zur Verfugung. Patienten und Methoden In einer retrospektiven Studie wurden die Behandlungsdaten von insgesamt 4 Patienten mit periorbitalem BCC analysiert, die mit Vismodegib behandelt worden waren. Die Patienten waren zu Therapiebeginn im Mittel 87 Jahre alt. Die maximale Tumorgrose zu Behandlungsbeginn war im Mittel 22,0 mm. Ergebnisse Das mediane Follow-up betrug 17 Monate. Die mediane Behandlungsdauer war 7,5 Monate. In 75 % konnte eine vollstandige klinische Remission erreicht werden. In 25 % war eine zwischenzeitliche Grosenstabilisierung erzielbar. Die haufigste beobachtete Nebenwirkung waren Muskelkrampfe. Schlussfolgerungen Vismodegib bietet eine effektive Behandlungsalternative fur Patienten mit periorbitalen BCC, die aus verschiedenen Grunden nicht fur eine operative Behandlung infrage kommen.

We present a case of bilateral choroidal abscesses due to a multidrug-resistant gram negative (4MRGN) Pseudomonas aeruginosa lung colonization in a patient with cystic fibrosis under immunosuppression after lung transplantation. Bilateral choroidal and subretinal abscesses were detected by funduscopy, ultrasound, magnetic resonance imaging (MRI) and phacovitrectomy and were accompanied by bilateral acute vision loss. The diagnosis was confirmed by intraoperative subretinal biopsy. Due to therapy resistance a bilateral enucleation for life-saving purposes was performed.

Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university–industry collaboration has grown over time. Moreover, we show how ideas from other scientific disciplines have been integrated into the FBDD paradigm. Keyword analysis showed that the field is organized into four interconnected practices: library design, fragment screening, computational methods, and optimization. This study highlights the importance of interactions among various individuals and institutions from diverse disciplines in newly emerging scientific fields. We study the organizational aspects of the development of fragment-based drug discovery (FBDD), using tools from bibliometrics.

Oculoplastic surgery places special demands on postoperative care because of the functional importance of the eyelids for the ocular surface. We present an overview of postoperative care after surgical eyelid interventions. All options, limits and the scientific evidence are discussed with a special focus on the treatment of postoperative edema, analgesia, infection prophylaxis and scar treatment.

Purpose Whether retinal degeneration is part of the degenerative processes in patients with Parkinson's disease (PD) is still unclear. This cross-sectional study was undertaken to compare the retinal morphology of patients with PD and healthy controls using spectral domain optical coherence tomography (SD-OCT) and scanning laser polarimetry (SLP). Methods Both eyes of patients with PD (n = 108) and healthy controls (n = 165) were examined using SD-OCT and SLP on the same day. Data on the thickness of the retinal nerve fibre layer (RNFL) of all quadrants and the macular area were acquired by OCT (Cirrus, Zeiss). The SLP device (Glaucoma diagnostics (GDx), Zeiss) measured the RNFL and calculated the nerve fibre index (NFI). All patients and probands were checked for concomitant ocular disorders by an ophthalmologist. Visual acuity, intraocular pressure (IOP), objective refraction and the anterior and posterior segment were assessed. Results Patients with PD showed a reduced macular volume and a reduced central subfield thickness in OCT examinations. The RNFL in the different quadrants did not differ significantly from that of controls. SLP data showed a reduced average RNFL thickness, a decreased thickness of the inferior quadrant and an increase of the NFI in patients with PD. Conclusion PD may be associated with reduced thickness and volume of the macula and a reduced thickness of the RNFL in the inferior quadrant of the retina. Investigations using SD-OCT and SLP revealed distinct but significant differences between patients with PD and healthy controls.

Purpose The study was performed to analyse the retina of patients with Parkinson's disease (PD) for morphological changes compared to healthy controls (HC) using spectral-domain optical coherence tomography (SD-OCT) and confocal scanning laser ophthalmoscopy. Methods We enrolled 108 patients with idiopathic PD and 165 HC. All study participants underwent an ophthalmological examination to exclude ophthalmological disorder potentially interfering with the retinal analyses. Peripapillary retinal nerve fibre layer (RNFL) thickness and macular thickness and volume were measured by a SD-OCT device (Heidelberg Spectralis®). Stereometric parameters of the optic disc were acquired by Heidelberg Retina Tomograph (HRT III). Results The RNFL thickness did not significantly differ between patients with PD and HC. The thickness of the central minimum and the centre of the macular area were significantly reduced in patients with PD, while the total macular volume did not significantly differ between the groups. Furthermore, we noted an inverse correlation between the central minimum thickness and the disease severity (assessed by the Hoehn and Yahr scale). HRT data showed no significant differences. Conclusion The HRT device and the RNFL measurements of the SD-OCT did not prove to be a clinically valid diagnostic tool to distinguish eyes of patients with PD and HC. However, the macular region and especially the foveola (central minimum) with the highest density of photoreceptor cells seem to be more sensitive and might be potential biomarkers.

The orbital volume after enucleation or evisceration might shrink over time due to atrophy of the orbital fat and connective tissue. This can lead to prosthesis misfit and an unsatisfactory cosmetic result. This so-called post enucleation socket syndrome (PESS) needs a secondary orbital volume augmentation. The techniques for orbital volume augmentation are secondary orbital implants or implant exchange, orbital floor implants or injectable augmentation. The surgical possibilities are described and discussed with special attention to indications and chances.

In der asthetischen Chirurgie erfordert eine Verjungung der Lider oft ein komplexes Vorgehen. Die Untersuchung der Unterlidfunktion und -laxitat ist eine Grundvoraussetzung, um das postoperative Risiko eines Ektropiums zu reduzieren. Mit steigendem Patientenalter und beginnender Unterliderschlaffung ist die laterale Kanthopexie ein effektiver Eingriff, welcher die Position der Unterlidkante bei postoperativ zunehmendem vertikalem Zug unterstutzt und das funktionelle sowie asthetische Ergebnis optimiert.

Protein kinases are one of the most targeted protein families in current drug discovery pipelines. They are implicated in many oncological, inflammatory, CNS-related and other clinical indications. Virtual screening is a computational technique with a diverse set of available tools that has been shown many times to provide novel starting points for kinase-directed drug discovery. This review starts with a concise overview of the function, structural features and inhibitory mechanisms of protein kinases. In addition to briefly reviewing the practical aspects of structure-based virtual screenings, we discuss several case studies to illustrate the state of the art in the virtual screening for type I, type II, allosteric (type III-V) and covalent (type VI) kinase inhibitors. With this review, we strive to provide a summary of the latest advances in the structure-based discovery of novel kinase inhibitors, as well as a practical tool to anyone who wishes to embark on such an endeavor.