A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.

We release a new, high quality data set of 1162 PDE10A inhibitors with experimentally determined binding affinities together with 77 PDE10A X-ray co-crystal structures from a Roche legacy project. This data set is used to compare the performance of different 2D- and 3D-machine learning (ML) as well as empirical scoring functions for predicting binding affinities with high throughput. We simulate use cases that are relevant in the lead optimization phase of early drug discovery. ML methods perform well at interpolation, but poorly in extrapolation scenarios-which are most relevant to a real-world application. Moreover, we find that investing into the docking workflow for binding pose generation using multi-template docking is rewarded with an improved scoring performance. A combination of 2D-ML and 3D scoring using a modified piecewise linear potential shows best overall performance, combining information on the protein environment with learning from existing SAR data.

Sex Differences in Cardiovascular Research: A Scientometric Analysis.

Background We sought to investigate sex-specific differences in authorship of cardiovascular research over the past decade. Methods and Results All 387 463 cardiovascular publications between 2010 and 2019 were retrieved from Web of Science. Articles increased from 19 960 to 29 604 articles per year (P>0.001). The number of articles written by female first authors increased by 76.3% (6434-11 343 articles) and by 35.0% for male first authors (13 526-18 261) (P<0.001). The first author was more likely to be a female author in articles with female last authors. The median impact factor (IF) for articles by female first authors was lower (2.46 [interquartile range, 7 1.11-4.03] versus 2.51 [interquartile range, 1.17-4.10]; P<0.001). Female authorship articles reached the highest IF in North America (average IF, 3.7), with the lowest in Africa (average IF, 1.8). Conclusions Publications in cardiovascular research have increased over the past decade, particularly by female authors. Female researchers are cited less often compared with their male peers. The IF remains lower for articles by female researchers.

Research in Atrial Fibrillation: A Scientometric Analysis Using the Novel Web Application SciPE.

OBJECTIVES: This study sought to determine the quantity and quality of publications in AF research using large-scale scientometric data analyses. BACKGROUND: Research in atrial fibrillation (AF) has increased over time. The increasing number of research papers makes it harder to identify relevant research work. METHODS: All 21,603 publications from 1945 to 2018 were retrieved from Web of Science and analyzed regarding geographical distribution of scientific output and international research cooperation. RESULTS: The total number of AF publications has significantly increased since the millennium change, from 3,063 (14.2%) in 1945 to 1999 to 18,540 (85.8%) publications in 2000 to 2018. AF research grew 10-fold compared with overall medical research since 1990 (ratio of AF publications to all publications: 0.02% (n = 99 of 410,701) in 1990 vs. 0.2% (n = 1,967 of 1,172,649) in 2018; p < 0.05). Quantitatively, the United States contributed 25.9% of AF research, followed by Japan (8.0%), Germany (7.8%), China (7.3%), and the United Kingdom (5.9%). In the all-time modified h-index, the United States ranked first (13.3% of all nations), followed by Canada (8.5%) and the United Kingdom (6.3%). In relation to population, Denmark was the best-rated nation, with the lowest number of inhabitants per publication (11,457), followed by Sweden (18,426) and the Netherlands (25,749), and per modified h-index (90,746), followed by Sweden (170,602) and the Netherlands (218,203). Measuring publications per research institute, Denmark again ranked first, with 19.2 publications per institute, followed by Italy (14.9) and Sweden (13.8). An intensive cooperation between nations was apparent. CONCLUSIONS: This study showed an increase in publication activity in AF research. The United States was the leading country in quantity of research efforts. Related to population and research institutes, Denmark ranked first.

Contemporary scientometric analyses using a novel web application: the science performance evaluation (SciPE) approach.

AIMS: We aimed at developing a structured study protocol utilizing the bibliographic web-application science performance evaluation (SciPE) to perform comprehensive scientometric analyses. METHODS AND RESULTS: Metadata related to publications derived from online databases were processed and visualized by transferring the information to an undirected multipartite graph and distinct partitioned sets of nodes. Also, institution-specific data were normalized and merged allowing precise geocoordinate positioning, to enable heatmapping and valid identification. As a result, verified, processed data regarding articles, institutions, journals, authors gender, nations and subject categories can be obtained. We recommend including the total number of publications, citations, the population, research institutions, gross domestic product, and the country-specific modified Hirsch Index and to form corresponding ratios (e.g., population/publication). Also, our approach includes implementation of bioinformatical methods such as heatmapping based on exact geocoordinates, simple chord diagrams, and the central implementation of specific ratios with plain visualization techniques. CONCLUSION: This protocol allows precise conduction of contemporaneous scientometric analyses based on bioinformatic and meta-analytical techniques, allowing to evaluate and contextualize scientific efforts. Data presentation with the depicted visualization techniques is mandatory for transparent and consistent analyses of research output across different nations and topics. Research performance can then be discussed in a synopsis of all findings.

Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor.

Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer's disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM's) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM's offer the potential of "use-dependent" attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM's. With these novel M1-PAM's, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM's have become available.

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases.

Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the γ-secretase inhibitor-based prodrugs 13a and 15a as substrates for γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-γ-Glu-γ-secretase inhibitor prodrug 13a (γ-GT-targeting and γ-GCT-targeting) but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the γ-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-γ-Glu-γ-secretase-inhibitor 13a.

The dynamics of Aß distribution after γ-secretase inhibitor treatment, as determined by experimental and modelling approaches in a wild type rat.

Inhibition of the enzyme(s) that produce the Amyloid beta (Aß) peptide, namely BACE and γ-secretase, is considered an attractive target for Alzheimer's disease therapy. However, the optimal pharmacokinetic-pharmacodynamic modelling method to describe the changes in Aß levels after drug treatment is unclear. In this study, turnover models were employed to describe Aß levels following treatment with the γ-secretase inhibitor RO5036450, in the wild type rat. Initially, Aß level changes in the brain, cerebral spinal fluid (CSF) and plasma were modeled as separate biological compartments, which allowed the estimation of a compound IC50 and Aß turnover. While the data were well described, the model did not take into consideration that the CSF pool of Aß most likely originates from the brain via the CSF drainage pathway. Therefore, a separate model was carried out, with the assumption that CSF Aß levels originated from the brain. The optimal model that described the data involved two brain Aß 40 sub-compartments, one with a rapid turnover, from which CSF Aß 40 is derived, and a second quasi-static pool of ~20%. Importantly, the estimated in vivo brain IC50 was in a good range of the in vitro IC50 (ratio, 1.4). In conclusion, the PK/PD models presented here are well suited for describing the temporal changes in Aß levels that occur after treatment with an Aß lowering drug, and identifying physiological parameters.

Morphologic and functional effects of gamma secretase inhibition on splenic marginal zone B cells.

The γ-secretase complex is a promising target in Alzheimer's disease because of its role in the amyloidogenic processing of ß-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oral γ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.

Aminothiazoles as γ-secretase modulators.

We herein report the discovery of a new γ-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aß) peptide production. Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aß42 peptide is shifted to smaller non-aggregating Aß peptides. Compound 15 reduced brain Aß42 in vivo in APPSwe transgenic mice at 30mg/kg p.o.

4-Substituted-7-N-alkyl-N-acetyl 2-aminobenzothiazole amides: drug-like and non-xanthine based A2B adenosine receptor antagonists.

7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.

Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties.

Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch-related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way.

Substituted 2-oxo-azepane derivatives are potent, orally active gamma-secretase inhibitors.

A hydroxamic acid screening hit 1 was elaborated to 5,5-dimethyl-2-oxoazepane derivatives exhibiting low nanomolar inhibition of gamma-secretase, a key proteolytic enzyme involved in Alzheimer's disease. Early ADME data showed a high metabolic clearance for the geminal dimethyl analogs which could be overcome by replacement with the bioisosteric geminal difluoro group. Synthesis and structure-activity relationship are discussed and in vivo active compounds are presented.

Generation of Abeta38 and Abeta42 is independently and differentially affected by familial Alzheimer disease-associated presenilin mutations and gamma-secretase modulation.

Alzheimer disease amyloid beta-peptide (Abeta) is generated via proteolytic processing of the beta-amyloid precursor protein by beta- and gamma-secretase. Gamma-secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid Abeta(42) and concomitantly increase the levels of the rather benign Abeta(38). Here we show that Abeta(42) and Abeta(38) generation occur independently from each other. The amount of Abeta(42) produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of gamma-secretase, appeared to correlate with the respective age of onset in patients. However, Abeta(38) levels did not show a negative correlation with the age of onset. Modulation of gamma-secretase activity by sulindac sulfide reduced Abeta(42) in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Abeta(42) or only rather subtle effects. Strikingly, even the mutations that showed no effect on Abeta(42) levels allowed a robust increase of Abeta(38) upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Abeta(42) and to decrease Abeta(38). For mutants that predominantly produce Abeta(42), the ability of fenofibrate to further increase Abeta(42) levels became diminished, whereas Abeta(38) levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Abeta(38) and Abeta(42) production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Abeta(42)-lowering capacity of gamma-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to gamma-secretase modulators.

Scaffold hopping.

The aim of scaffold hopping is to discover structurally novel compounds starting from known active compounds by modifying the central core structure of the molecule. Scaffold hopping is a central task of modern medicinal chemistry requiring a multitude of techniques, which are discussed in this article. Their application has led to several molecules with chemically completely different core structures, and yet binding to the same receptor. Computational approaches for scaffold hopping highlight the challenges of the field that are still unsolved.:

An Antibody-Catalyzed Allylic Sulfoxide-Sulfenate Rearrangement.

Antibodies SZ-cis-39C11 and SZ-trans-28F8, which were elicited in response to N-aryl-3-methoxyphenyl proline derivatives, catalyze the [2,3]-sigmatropic rearrangement of allylic sulfoxides to sulfenates. Reduction of the sulfenates with dithiothreitol in situ yields allylic alcohols as the final product. The antibodies achieve rate accelerations in the range 10(2)-10(3) over background and exhibit distinctive hapten-dependent substrate specificity and enantio- and diastereoselectivity. Of particular note is the effective chirality transfer from the sulfoxide center to the product alcohol in the SZ-cis-39C11-catalyzed conversion of (Z)-2-(4-methoxyphenyl)-but-2-en-1-yl 4-nitrophenyl sulfoxide. These properties can be contrasted with those of bovine serum albumin (BSA) which accelerates the same reactions to a comparable extent but does not discriminate between substrate isomers. Partitioning of substrate from aqueous solution into the less polar environment of the protein pocket can account for much of the observed rate enhancement, whereas specific conformational constraints programmed by the haptens must orient the flexible substrate within the induced antibody-combining sites so as to favor certain reaction pathways over others. These studies thus expand the scope of antibody catalysis to an important new class of pericyclic reactions and illustrate how medium effects can be exploited together with conformational constraint to control reactivity and selectivity.