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Osteoarthritis (OA) is a chronic and degenerative joint disease affecting more than 500 million patients worldwide with no disease-modifying treatment approved to date. Several publications report on the transforming growth factor β-activated kinase 1 (TAK1) as a potential molecular target for OA, with complementary anti-catabolic and anti-inflammatory effects. We report herein on the development of TAK1 inhibitors with physicochemical properties suitable for intra-articular injection, with the aim to achieve high drug concentration at the affected joint, while avoiding severe toxicity associated with systemic inhibition. More specifically, reducing solubility by increasing crystallinity, while maintaining moderate lipophilicity proved to be a good compromise to ensure high and sustained free drug exposures in the joint. Furthermore, structure-based design allowed for an improvement of selectivity versus interleukin-1 receptor-associated kinases 1 and 4 (IRAK1/4). Finally, TAK-756 was discovered as a potent TAK1 inhibitor with good selectivity versus IRAK1/4 as well as excellent intra-articular pharmacokinetic properties.

Background: Patients with open fractures often experience complications during their injury. The treatments incur high costs. Interdisciplinary cooperation between different medical disciplines may improve treatment outcomes. Such cooperation has not yet been envisaged in the German health care system., Objective: The aim of the study is to improve the treatment of fractures with open soft tissue damage or postoperative complications in terms of duration and sustainability in a region in northwest Germany. Largely standardized diagnostics and therapy are intended to optimize processes in hospitals. In addition, a reduction in the duration of treatment and treatment costs is to be achieved., Methods: Using a digital platform, physicians from 31 hospitals present patient cases to an interdisciplinary group of experts from the fields of plastic surgery, infectiology, hygiene, and others. The group of experts from the environment of the University Hospital Münster promptly makes a joint treatment recommendation for the individual case. The plan is to examine 3300 patients with open fractures or surgical complications. As consortium partners, there are also 3 statutory health insurance companies. The extent to which the therapy recommendations are effective and contribute to cost reduction in the health care system will be empirically investigated in a stepped-wedge cluster-randomized design. In addition, medical and nonmedical professional groups involved in the project will be asked about their work in the project (in total, 248 clinic employees). The primary outcome is the complication rate of open fractures or the occurrence of postoperative complications. As secondary outcomes, the number of antibiotics administered, limb function, and quality of life will be assessed. The health economic evaluation refers to the costs of health services and absenteeism. For the work-related evaluation, workload, work engagement, work-related resources, readiness for technology, and ergonomic aspects of the new telemedical technology will be collected. In addition, clinic employees will give their assessments of the success of the project in a structured telephone interview based on scaled and open-ended questions., Results: The project started in June 2022; data collection started in April 2023. As of mid-June 2024, data from 425 patients had been included. In total, 146 members of staff had taken part in the questionnaire survey and 15 had taken part in the interviews., Conclusions: Standardized treatment pathways in the standard care of patients with open fractures and postoperative infections will be established to reduce complications, improve chances of recovery, and reduce costs. Unnecessary and redundant treatment steps will be avoided through standardized diagnostics and therapy. The interdisciplinary treatment perspective allows for a more individualized therapy. In the medium term, outpatient or inpatient treatment centers specialized in the patient group could be set up where the new diagnostic and therapeutic pathways could be competently applied., Trial Registration: German Clinical Trials Register DRKS00031308; https://drks.de/search/de/trial/DRKS00031308., International Registered Report Identifier (irrid): DERR1-10.2196/57820., (©Steffen Rosslenbroich, Marion Laumann, Joachim Hasebrook, Sibyll Rodde, John Grosser, Wolfgang Greiner, Tobias Hirsch, Stefan Windrich, Michael J Raschke. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.09.2024.)

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic p K a is significantly lower than the basic p K a . Through concordance of measured and calculated p K a and log P , we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative Δp K a . These nonclassical zwitterions are characterized by a weak acidic and basic p K a and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

Covalent inhibition offers many advantages over non-covalent inhibition, but covalent warhead reactivity must be carefully balanced to maintain potency while avoiding unwanted side effects. While warhead reactivities are commonly measured with assays, a computational model to predict warhead reactivities could be useful for several aspects of the covalent inhibitor design process. Studies have shown correlations between covalent warhead reactivities and quantum mechanic (QM) properties that describe important aspects of the covalent reaction mechanism. However, the models from these studies are often linear regression equations and can have limitations associated with their usage. Applications of machine learning (ML) models to predict covalent warhead reactivities with QM descriptors are not extensively seen in the literature. This study uses QM descriptors, calculated at different levels of theory, to train ML models to predict reactivities of covalent acrylamide warheads. The QM/ML models are compared with linear regression models built upon the same QM descriptors and with ML models trained on structure-based features like Morgan fingerprints and RDKit descriptors. Experiments show that the QM/ML models outperform the linear regression models and the structure-based ML models, and literature test sets demonstrate the power of the QM/ML models to predict reactivities of unseen acrylamide warhead scaffolds. Ultimately, these QM/ML models are effective, computationally feasible tools that can expedite the design of new covalent inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Extracellular vesicles (EVs) are nanosized intercellular messengers that bear enormous application potential as biological drug delivery vehicles. Much progress has been made for loading or decorating EVs with proteins, peptides or RNAs using genetically engineered donor cells, but post-isolation loading with synthetic drugs and using EVs from natural sources remains challenging. In particular, quantitative and unambiguous data assessing whether and how small molecules associate with EVs versus other components in the samples are still lacking. Here we describe the systematic and quantitative characterisation of passive EV loading with small molecules based on hydrophobic interactions - either through direct adsorption of hydrophobic compounds, or by membrane anchoring of hydrophilic ligands via cholesterol tags. As revealed by single vesicle imaging, both ligand types bind to CD63 positive EVs (exosomes), however also non-specifically to other vesicles, particles, and serum proteins. The hydrophobic compounds Curcumin and Terbinafine aggregate on EVs with no apparent saturation up to 10 6 -10 7 molecules per vesicle as quantified by liquid chromatography - high resolution mass spectrometry (LC-HRMS). For both compounds, high density EV loading resulted in the formation of a population of large, electron-dense vesicles as detected by quantitative cryo-transmission electron microscopy (TEM), a reduced EV cell uptake and a toxic gain of function for Curcumin-EVs. In contrast, cholesterol tagging of a hydrophilic mdm2-targeted cyclic peptide saturated at densities of ca 10 4 -10 5 molecules per vesicle, with lipidomics showing addition to, rather than replacement of endogenous cholesterol. Cholesterol anchored ligands did not change the EVs' size or morphology, and such EVs retained their cell uptake activity without inducing cell toxicity. However, the cholesterol-anchored ligands were rapidly shed from the vesicles in presence of serum. Based on these data, we conclude that (1) both methods allow loading of EVs with small molecules but are prone to unspecific compound binding or redistribution to other components if present in the sample, (2) cholesterol anchoring needs substantial optimization of formulation stability for in vivo applications, whereas (3) careful titration of loading densities is warranted when relying on hydrophobic interactions of EVs with hydrophobic compounds to mitigate changes in physicochemical properties, loss of EV function and potential cell toxicity., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also their passive membrane permeability. As the "journey" through membranes cannot be monitored experimentally, little is known about the underlying process, which hinders rational design. Here, we use molecular simulations to uncover how cyclic peptides permeate a membrane. We show that side chains can act as "molecular anchors", establishing the first contact with the membrane and enabling insertion. Once inside, the peptides are positioned between headgroups and lipid tails─a unique polar/apolar interface. Only one of two distinct orientations at this interface allows for the formation of the permeable "closed" conformation. In the closed conformation, the peptide crosses to the lower leaflet via another "anchoring" and flipping mechanism. Our findings provide atomistic insights into the permeation process of flexible cyclic peptides and reveal design considerations for each step of the process.

We herein report the development of an automation platform for rapid purification and quantification of chemical libraries including reformatting of chemical matter to 10 mM DMSO stock solutions. This fully integrated workflow features tailored conditions for preparative reversed-phase (RP) HPLC-MS on microscale based on analytical data, online fraction QC and CAD-based quantification as well as automated reformatting to enable rapid purification of chemical libraries. This automated workflow is entirely solution-based, eliminating the need to weigh or handle solids. This increases process efficiency and creates a link between high-throughput synthesis and profiling of novel chemical matter with respect to biological and physicochemical properties in relevant assays., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Cyclic peptides have the potential to vastly extend the scope of druggable proteins and lead to new therapeutics for currently untreatable diseases. However, cyclic peptides often suffer from poor bioavailability. To uncover design principles for permeable cyclic peptides, a promising strategy is to analyze the conformational dynamics of the peptides using molecular dynamics (MD) and Markov state models (MSMs). Previous MD studies have focused on the conformational dynamics in pure aqueous or apolar environments to rationalize membrane permeability. However, during the key steps of the permeation through the membrane, cyclic peptides are exposed to interfaces between polar and apolar regions. Recent studies revealed that these interfaces constitute the free energy minima of the permeation process. Thus, a deeper understanding of the behavior of cyclic peptides at polar/apolar interfaces is desired. Here, we investigate the conformational and kinetic behavior of cyclic decapeptides at a water/chloroform interface using unbiased MD simulations and MSMs. The distinct environments at the interface alter the conformational equilibrium as well as the interconversion kinetics of cyclic peptide conformations. For peptides with low population of the permeable conformation in aqueous solution, the polar/apolar interface facilitates the interconversion to the closed conformation, which is required for membrane permeation. Comparison to unbiased MD simulations with a POPC bilayer reveals that not only the conformations but also the orientations are relevant in a membrane system. These findings allow us to propose a permeability model that includes both 'prefolding' and 'non-prefolding' cyclic peptides - an extension that can lead to new design considerations for permeable cyclic peptides., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Cyclic peptides have received increasing attention over the recent years as potential therapeutics for "undruggable" targets. One major obstacle is, however, their often relatively poor bioavailability. Here, we investigate the structure-permeability relationship of 24 cyclic decapeptides that share the same backbone N-methylation pattern but differ in their side chains. The peptides cover a large range of values for passive membrane permeability as well as lipophilicity and solubility. To rationalize the observed differences in permeability, we extracted for each peptide the population of the membrane-permeable conformation in water from extensive explicit-solvent molecular dynamics simulations and used this as a metric for conformational rigidity or "prefolding." The insights from the simulations together with lipophilicity measurements highlight the intricate interplay between polarity/lipophilicity and flexibility/rigidity and the possible compensating effects on permeability. The findings allow us to better understand the structure-permeability relationship of cyclic peptides and extract general guiding principles.

Conformational equilibria are at the heart of drug design, yet their energetic description is often hampered by the insufficient accuracy of low-cost methods. Here we present a flexible and semi-automatic workflow based on quantum chemistry, ReSCoSS, designed to identify relevant conformers and predict their equilibria across different solvent environments in the Conductor-like Screening Model for Real Solvents (COSMO-RS) framework. We demonstrate the utility and accuracy of the workflow through conformational case studies on several drug-like molecules from literature where relevant conformations are known. We further show that including ReSCoSS conformers significantly improves COSMO-RS based predictions of physicochemical properties over single-conformation approaches. ReSCoSS has found broad adoption in the in-house drug discovery and development work streams and has contributed to establishing quantum-chemistry methods as a strategic pillar in ligand discovery.

The acid-base dissociation constant, p K a , is a key parameter to define the ionization state of a compound and directly affects its biopharmaceutical profile. In this study, we developed a novel approach for p K a prediction using rooted topological torsion fingerprints in combination with five machine learning (ML) methods: random forest, partial least squares, extreme gradient boosting, lasso regression, and support vector regression. With a large and diverse set of 14 499 experimental p K a values, p K a models were developed for aliphatic amines. The models demonstrated consistently good prediction statistics and were able to generate accurate prospective predictions as validated with an external test set of 726 p K a values (RMSE 0.45, MAE 0.33, and R 2 0.84 by the top model). The factors that may affect prediction accuracy and model applicability were carefully assessed. The results demonstrated that rooted topological torsion fingerprints coupled with ML methods provide a promising approach for developing accurate p K a prediction models.

Background: All statistics on the development of demand for care for multimorbid elderly patients highlight the acute pressure to act to adequately respond to the expected increase in geriatric patient population in the next 15 years. Against this background, great importance must be attached to the improvement of cross-occupational group and cross-sector treatment of these patients. In addition, many professionals in the health care sector often have little knowledge about the special treatment and care needs of the elderly., Objective: The Quality Network of Geriatric Medicine in north-west Germany is the body responsible for the project; with its member organizations, it provides care for over 400,000 inpatients and is thus one of the largest associations for geriatrics in Germany. The Quality Network conducts binding evaluated qualification measures for staff involved in the treatment and care of multimorbid elderly patients. The training offers are especially intended for staff who have not yet been trained in working with elderly patients. This approach is intended to improve the expertise of various occupational groups on different hierarchy levels, to include patients and their family members in the evaluation process, and to initiate changes within the organizations., Methods: Various instruments are used in the evaluation of qualification measures: besides written surveys and questionnaires, structured work groups (consensus groups) and interviews are conducted. The evaluation starts before the qualification measures to determine the starting point and then continues during the measure and after its completion. This allows major findings to be integrated directly into the ongoing qualification program. At least 100 trainings on geriatric topics, 80 consensus groups, and 120 patients (and family members) are going to be included in the study., Results: The evaluation of the educational initiative is funded by the State of Northrhine-Westfalia (Germany; LZG TG 71 001 / 2015 and LZG TG 71 002 / 2015). The results of the study will be published after review and approval by the state authorities - presumably by the end of 2019. The before and after comparison of the treatment-related outcomes at the beginning and near the completion of the educational initiative gives insights into how transfer-oriented education can improve the treatment of elderly patients across sector lines for inpatients as well as outpatients. The evaluation of the implementation of educational content in day-to-day work and occupational groups is to facilitate recommendations about economically sensible use of educational resources and about further adjustments to the training content., Conclusions: The evaluation develops the foundation for targeted and needs-oriented qualification measures as well as transfer in cross-sector, multiprofessional networks. Instruments and results will be published and provided to other health care networks and institutions. The Quality Network will implement the results of the evaluation process in its member institutions., International Registered Report Identifier (irrid): DERR1-10.2196/11067., (©Daisy Huenefeld, Sibyll Rodde, Gertrud Bureick, Barbara Elkeles, Joachim Hasebrook. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 03.05.2019.)

Recent advances in the development of low-cost quantum chemical methods have made the prediction of conformational preferences and physicochemical properties of medium-sized drug-like molecules routinely feasible, with significant potential to advance drug discovery. In the context of the SAMPL6 challenge, macroscopic pKa values were blindly predicted for a set of 24 of such molecules. In this paper we present two similar quantum chemical based approaches based on the high accuracy calculation of standard reaction free energies and the subsequent determination of those pKa values via a linear free energy relationship. Both approaches use extensive conformational sampling and apply hybrid and double-hybrid density functional theory with continuum solvation to calculate free energies. The blindly calculated macroscopic pKa values were in excellent agreement with the experiment.

University hospitals are involved in the care of critically ill patients, pregraduate and postgraduate education, and medical research with an increasing demand on physicians due to a higher burden of disease. The number of female physicians is increasing; however, young female physicians are less willing to work at university hospitals under the given conditions. They often do not find appropriate working conditions in mostly hierarchically structured university hospitals. Institutional structures involuntarily erect barriers against the recruitment, retention, and career progression of women. Gendered working conditions remain firmly fixed, and this is even more challenging - overt discrimination has been replaced by less visible mostly implicit stereotypes and prejudices against women. Having children is an additional "career stopper" for female physicians: those with children are less likely to be promoted and have a lower income. Regulatory measures should act in several directions: cultural gender equality policies, family support policies, and active work policies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It is widely understood that QSAR models greatly improve if more data are used. However, irrespective of model quality, once chemical structures diverge too far from the initial data set, the predictive performance of a model degrades quickly. To increase the applicability domain we need to increase the diversity of the training set. This can be achieved by combining data from diverse sources. Public data can be easily included; however, proprietary data may be more difficult to add due to intellectual property concerns. In this contribution, we will present a method for the collaborative development of linear regression models that addresses this problem. The method differs from other past approaches, because data are only shared in an aggregated form. This prohibits access to individual data points and therefore avoids the disclosure of confidential structural information. The final models are equivalent to models that were built with combined data sets.

Background: All European countries need to increase the number of health professionals in the near future. Most efforts have not brought the expected results so far. The current notion is that this is mainly related to the fact that female physicians will clearly outnumber their male colleagues within a few years in nearly all European countries. Still, women are underrepresented in leadership and research positions throughout Europe., Objectives: The MedGoFem project addresses multiple perspectives with the participation of multiple stakeholders. The goal is to facilitate the implementation of Gender Equality Plans (GEP) in university hospitals; thereby, transforming the working conditions for women working as researchers and highly qualified physicians simultaneously. Our proposed innovation, a crosscutting topic in all research and clinical activities, must become an essential part of university hospital strategic concepts., Methods: We capture the current status with gender-sensitive demographic data concerning medical staff and conduct Web-based surveys to identify cultural, country-specific, and interdisciplinary factors conducive to women's academic success. Individual expectations of employees regarding job satisfaction and working conditions will be visualized based on "personal construct theory" through repertory grids. An expert board working out scenarios and a gender topic agenda will identify culture-, nation-, and discipline-specific aspects of gender equality. University hospitals in 7 countries will establish consensus groups, which work on related topics. Hospital management supports the consensus groups, valuates group results, and shares discussion results and suggested measures across groups. Central findings of the consensus groups will be prepared as exemplary case studies for academic teaching on research and work organization, leadership, and management., Results: A discussion group on gender equality in academic medicine will be established on an internationally renowned open-research platform. Project results will be published in peer-reviewed journals with high-impact factors. In addition, workshops on gender dimension in research using the principles of Gendered Innovation will be held. Support and consulting services for hospitals will be introduced in order to develop a European consulting service., Conclusions: The main impact of the project will be the implementation of innovative GEP tailored to the needs of university hospitals, which will lead to measurable institutional change in gender equality. This will impact the research at university hospitals in general, and will improve career prospects of female researchers in particular. Simultaneously, the gender dimension in medical research as an innovation factor and mandatory topic will be strengthened and integrated in each individual university hospital research activity. Research funding organizations can use the built knowledge to include mandatory topics for funding applications to enforce the use and implementation of GEP in university hospitals., (©Joachim Hasebrook, Klaus Hahnenkamp, Wolfgang F.F.A. Buhre, Dianne de Korte-de Boer, Ankie E.W. Hamaekers, Bibiana Metelmann, Camila Metelmann, Marina Bortul, Silvia Palmisano, Jannicke Mellin-Olsen, Andrius Macas, Janusz Andres, Anna Prokop-Dorner, Tomáš Vymazal, Juergen Hinkelmann, Sibyll Rodde, Bettina Pfleiderer. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 02.08.2017.)

Background: University hospitals make up the backbone of medical and economic services of hospitals in Germany: they qualify specialist physicians, ensure medical research, and provide highly specialized maximum medical care, which other hospitals cannot undertake. In addition to this assignment, medical research and academic teaching must be managed despite a growing shortage of specialist physicians. By the year 2020, the need for the replacement of retired physicians and increased demand will total 30,000 positions. The situation will become more difficult because, on the whole, patients are becoming older and sicker and because specialist physicians are able to find more attractive working conditions in smaller hospitals, abroad, or outside of curative medicine., Objective: In order to retain sufficient qualified employees, major improvements in quality are required in terms of working and training conditions. For this purpose, a sustainable innovation process is necessary, which incorporates solutions from outside of the health care sector in order to be able to learn from experiences and mistakes from other industries. The FacharztPlus project aims to find suitable measures in order to retain specialist physicians for more years after the completion of 5 years of professional training. This should determine the suitability of additional qualifications alongside the professional career and an expertise-related work organization oriented to different stages of life., Methods: Structured interviews, surveys, and repertory grids are used as preparation for cross-industry expert panels to create future work scenarios for university hospitals. Industries involved are harbor logistics (container terminal), airports, and digitized industrial production ("industry 4.0") because these industries are also facing a shortage of qualified staff and have to respond to rapidly changing demands. Based on the experts' scenarios, consensus groups will be established in each university hospital trying to reach consensus about the implementation of relevant factors in order to improve employee retention., Results: We expect these consensus groups to develop and introduce measures for more structured training procedures, individual and team incentives, organizational guidelines for better recruiting and retention in hospitals, models of flexible and attractive working conditions including shift work and vacation planning, and use of new learning tools (eg, tablet PCs and mobile phones)., Conclusions: All measures are implemented in the Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine at the University Hospital Muenster (UKM) with approximately 150 physicians and in the further 44 departments of the UKM and 22 teaching hospitals, which all together employ more than 5000 physicians. The measures will also be implemented at the university hospitals in Aachen, Rostock, and Greifswald. All decisions and measures will be discussed with representatives from hospital management and professional associations. Results will be presented at conferences and published in journals., Competing Interests: Conflicts of Interest: None declared., (©Joachim Paul Hasebrook, Jürgen Hinkelmann, Thomas Volkert, Sibyll Rodde, Klaus Hahnenkamp. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 21.12.2016.)

The ionization state of drugs influences many pharmaceutical properties such as their solubility, permeability, and biological activity. It is therefore important to understand the structure property relationship for the acid-base dissociation constant pKa during the lead optimization process to make better-informed design decisions. Computational approaches, such as implemented in MoKa, can help with this; however, they often predict with too large error especially for proprietary compounds. In this contribution, we look at how retraining helps to greatly improve prediction error. Using a longitudinal study with data measured over 15 years in a drug discovery environment, we assess the impact of model training on prediction accuracy and look at model degradation over time. Using the MoKa software, we will demonstrate that regular retraining is required to address changes in chemical space leading to model degradation over six to nine months.

The aim of this study was to understand which parameters are responsible for the selective modulation of compounds solubility in simulated intestinal fluids. The solubility of 25 chemically diverse reference compounds was measured in simulated intestinal fluid (FaSSIF-V2) and in aqueous phosphate and maleate buffers. Electrostatic interactions between compounds and the bio-relevant medium components seem to explain the different solubility behavior observed for acids and bases. The solubility of ionized acids is not increased in FaSSIF-V2 probably due to electrostatic repulsions with the media components. Lipophilicity plays an important role but mainly for charged bases with a logP>4 (or logD(6.5)>1.9). When the aqueous solubility is mainly driven by lipophilicity, the FaSSIF-V2 components seem to improve the solubility of basic compounds to a greater extent than for compounds whose solubility is limited by crystal packing. These results suggest that ionization, lipophilicity and crystal packing play important but peculiar roles in controlling solubility in FaSSIF-V2 compared to that in aqueous buffer and this information could be useful to guide medicinal chemists and formulation scientists., (Copyright © 2010 Elsevier B.V. All rights reserved.)