Pandemic Drugs at Pandemic Speed: Infrastructure for Accelerating COVID-19 Drug Discovery with Hybrid Machine Learning- and Physics-based Simulations on High Performance Computers

The race to meet the challenges of the global pandemic has served as a reminder that the existing drug discovery process is expensive, inefficient and slow. There is a major bottleneck screening the vast number of potential small molecules to shortlist lead compounds for antiviral drug development. New opportunities to accelerate drug discovery lie at the interface between machine learning methods, in this case, developed for linear accelerators, and physics-based methods. The two in silico methods, each have their own advantages and limitations which, interestingly, complement each other. Here, we present an innovative infrastructural development that combines both approaches to accelerate drug discovery. The scale of the potential resulting workflow is such that it is dependent on supercomputing to achieve extremely high throughput. We have demonstrated the viability of this workflow for the study of inhibitors for four COVID-19 target proteins and our ability to perform the required large-scale calculations to identify lead antiviral compounds through repurposing on a variety of supercomputers

Red-Emitting Dibenzodiazepinone Derivatives as Fluorescent Dualsteric Probes for the Muscarinic Acetylcholine M2 Receptor

Fluorescently labeled dibenzodiazepinone-type muscarinic acetylcholine receptor (MR) antagonists, including dimeric ligands, were prepared using red-emitting cyanine dyes. Probes containing a fluorophore with negative charge showed high M2R affinities (pKi (radioligand competition binding): 9.10-9.59). Binding studies at M1 and M3-M5 receptors indicated a M2R preference. Flow cytometric and high-content imaging saturation and competition binding (M1R, M2R, and M4R) confirmed occupation of the orthosteric site. Confocal microscopy revealed that fluorescence was located mainly at the cell membrane (CHO-hM2R cells). Results from dissociation and saturation binding experiments (M2R) in the presence of allosteric M2R modulators (dissociation: W84, LY2119620, and alcuronium; saturation binding: W84) were consistent with a competitive mode of action between the fluorescent probes and the allosteric ligands. Taken together, these lines of evidence indicate that these ligands are useful fluorescent molecular tools to label the M2R in imaging and binding studies and suggest that they have a dualsteric mode of action

IMPECCABLE: Integrated Modeling PipelinE for COVID Cure by Assessing Better LEads

The drug discovery process currently employed in the pharmaceutical industry typically requires about 10 years and $2–3 billion to deliver one new drug. This is both too expensive and too slow, especially in emergencies like the COVID-19 pandemic. In silico methodologies need to be improved both to select better lead compounds, so as to improve the efficiency of later stages in the drug discovery protocol, and to identify those lead compounds more quickly. No known methodological approach can deliver this combination of higher quality and speed. Here, we describe an Integrated Modeling PipEline for COVID Cure by Assessing Better LEads (IMPECCABLE) that employs multiple methodological innovations to overcome this fundamental limitation. We also describe the computational framework that we have developed to support these innovations at scale, and characterize the performance of this framework in terms of throughput, peak performance, and scientific results. We show that individual workflow components deliver 100 × to 1000 × improvement over traditional methods, and that the integration of methods, supported by scalable infrastructure, speeds up drug discovery by orders of magnitudes. IMPECCABLE has screened ∼ 1011 ligands and has been used to discover a promising drug candidate. These capabilities have been used by the US DOE National Virtual Biotechnology Laboratory and the EU Centre of Excellence in Computational Biomedicine

Failed back surgeries and minnesota multiphasic personality inventory (MMPI) profiles

MMPI profiles were evaluated for 105 prospective surgical patients who had previously undergone surgery or other procedures for treatment of back pain. Patients were classified into groups having undergone zero, one, two, three, or four or more previous surgeries. While all groups demonstrated a characteristic somatogenic profile, none of the MMPI validity or clinical scales significantly differentiated the groups and there was no relationship between increased number of surgeries and MMPI scale characteristics. These results support the nonoptimistic prognostication of the somatogenic MMPI profile for surgical intervention for back pain but show no clear relationship of MMPI profile characteristics to degree of experience of previously failed surgery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44850/1/10880_2005_Article_BF01999744.pd

Immunphänotypisierung von Lymphocyten-Subpopulationen mit monoklonalen Antikörpern im analytischen Durchflußcytometer: Evaluierung von Methodik und Referenzbereichen

Peer Reviewe

Introduction of a web portal for an Individual Health Management and observational health data sciences

Dieter Melchart,1,2 Axel Eustachi,1 Stephan Gronwald,3 Erich Wühr,3 Kristina Wifling,1 Beatrice E Bachmeier1,4 1Competence Centre for Complementary Medicine and Naturopathy, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; 2Institute for Complementary and Integrative Medicine, University Hospital Zurich and University of Zurich, Zurich, Switzerland; 3Applied Health Care Science, Deggendorf Institute of Technology, Deggendorf, Germany; 4Institute of Laboratory Medicine, Ludwig-Maximilians-University, Munich, Germany Background: There is a global trend to a stronger active involvement of persons in the maintenance and restoring of health. The Competence Centre for Complementary Medicine and Naturopathy (CoCoNat) of the Technical University of Munich (TUM) has developed a lifestyle concept to enable each individual to manage his or her health – Individual Health Management (IHM) – and a web-based health portal named Virtual Tool for Education, Reporting, Information and Outcomes (VITERIO®), which addresses these needs for practice and research. Objectives: The objectives of this study were to establish a core set of questionnaires for a self-assessment program on certain risk indications and comprehensive protection factors of health and to develop and enhance 1) tools for individual feedback, longitudinal self-monitoring, self-assessment, and (self-)care-planning; 2) training packages; 3) open notes and records for provider and patient; and 4) tools for monitoring groups and single participants in various indicators for individual coaching and scientific evaluation. Methods: The CoCoNat of TUM, Faculty for Applied Health Science of Technische Hochschule Deggendorf, VITERIO® company, IHM campus network, and Erich Rothenfußer Foundation, Munich, provide a consortium responsible for content, research strategy, technical production and implication, postgraduate education for IHM coaches, implementation of IHM in various settings, and funding resources. Results: A data set of indicators for health screening and self-monitoring of findings, symptoms, health behavior, and attitudes are integrated into a web-based health portal named VITERIO®. The article introduces some implemented graphical solutions of developed tools and gives examples for daily use. Conclusion: Behavioral change and adaptation in attitudes and personal values are difficult issues of health education and lifestyle medicine. To address this problem best, the implementation of a patient-centric, performance measures-based program including open records and a blended learning concept were elaborated. The combination of an individual web-based health portal with personal coaching allows the implementation of IHM in everyday practice. Keywords: lifestyle program, Individual Health Management, IHM, blended learning, performance measures, web-based health portal, adherenc

Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif

Histamine H4 receptor (H4R) orthologues are G‐protein coupled receptors (GPCRs) that exhibit species‐dependent basal activity: In contrast to the basally inactive mouse H4R (mH4R), human H4R (hH4R) shows a high degree of basal activity. We have performed long‐time‐scale molecular‐dynamics simulations and rigidity analyses on wild‐type hH4R, the experimentally characterized hH4R variants S179M, F169V, F169V+S179M, F168A, and on mH4R to investigate the molecular nature of differential basal activity. H4R variant‐dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F16945.55 dips into the orthosteric binding pocket only in the case of hH4R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H4R activation that are of importance for other GPCRs