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On modelling disordered crystal structures through restraints from molecule-in-cluster computations,and distinguishing static and dynamic disorder
No full textDistinguishing disorder into static and dynamic based on multi-temperature
X-ray or neutron diffraction experiments is the current state of the art, but is
only descriptive, not predictive. Here, several disordered structures are revisited
from the Cambridge Crystallographic Data Center ‘drug subset’, the Cambridge
Structural Database and own earlier work, where experimental intensities of
Bragg diffraction data were available. Using the molecule-in-cluster approach,
structures with distinguishable conformations were optimized separately, as
extracted from available or generated disorder models of the respective
disordered crystal structures. Re-combining these ‘archetype structures’ by
restraining positional and constraining displacement parameters for conventional
least-squares refinement, based on the optimized geometries, then often
achieves a superior fit to the experimental diffraction data compared with
relying on experimental information alone. It also simplifies and standardizes
disorder refinement. Ten example structures were analysed. It is observed
that energy differences between separate disorder conformations are usually
within a small energy window of RT (T = crystallization temperature). Further
computations classify disorder into static or dynamic, using single experiments
performed at one single temperature, and this was achieved for propionamide
Mild and robust Stille reactions in water using ppm levels of a new triphenylphosphine-based palladacycle
No full textAn inexpensive and new triphenylphosphine-based palladacycle has been developed as a pre-catalyst leading to highly
effective Stille cross coupling reactions in water under mild conditions. Only 500-1000 ppm of Pd suffices for couplings involving a variety of aryl/heteroaryl halides with aryl/hetaryl stannanes. Several drug intermediates can be prepared using this catalyst in aqueous nanoreactors formed by 2 wt % Brij-30 in water
“TPG-lite”: A new, simplified “designer” surfactant for general use in synthesis under micellar catalysis conditions in recyclable water
No full textUsing the oxidized, carboxylic acid-containing form of MPEG-750, esterification with racemic vitamin E affords a new surfactant (TPG-lite) that functions as an enabling, nanoreactor-forming amphiphile for use in many types of important reactions in synthesis. The presence of a single ester bond is suggestive of simplified treatment as a component of (eventual) reaction waste water, after recycling. Many types of reactions, including aminations, Suzuki-Miyaura, SNAr, and several others are compared directly with TPGS-750-M, leading to the conclusion that TPG-lite can function as an equivalent nanomicelle-forming surfactant in water. Prima facie evidence amassed via DLS and cryo-TEM analyses support these experimental observations. In silic
Genetic engineering of Chromobacterium vaccinii DSM 25150 for improved production of FR900359
No full textThe cyclic depsipeptide FR900359 is a potent and selective Gq protein inhibitor. This pharmacological activity has raised strong interest in FR900359. However, the access to the compound was so far challenging, as it could only be isolated from the leaves of the plant Ardisia crenata in a tedious and low-yielding process. Here we describe the identification and genetic engineering of a bacterial producers of FR900359, Chromobacterium vaccinii DSM 25150. Further, genetic modifications to the strain are described which result in increased production and higher isolated yields of FR900359
Alternative Complement Pathway Inhibition Does Not Abrogate Meningococcal Killing by Serum of Vaccinated Individuals
No full textDysregulation of complement activation causes a number of diseases, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. These conditions can be treated with monoclonal antibodies (mAbs) that bind to the complement component C5 and prevent formation of the membrane attack complex (MAC). While MAC is involved in uncontrolled lysis of erythrocytes in these patients, it is also required for serum bactericidal activity (SBA), i.e. clearance of encapsulated bacteria. Therefore, terminal complement blockage in these patients increases the risk of invasive disease by Neisseria meningitidis more than 1000-fold compared to the general population, despite obligatory vaccination. It is assumed that alternative instead of terminal pathway inhibition reduces the risk of meningococcal disease in vaccinated individuals. To address this, we investigated the SBA with alternative pathway inhibitors. Serum was collected from adults before and after vaccination with a meningococcal serogroup A, C, W, Y capsule conjugate vaccine and tested for meningococcal killing in the presence of factor B and D, C3, C5 and MASP-2 inhibitors. B meningococci were not included in this study since the immune response against protein-based vaccines is more complex. Unsurprisingly, inhibition of C5 abrogated killing of meningococci by all sera. In contrast, both factor B and D inhibitors affected meningococcal killing in sera from individuals with low, but not with high bactericidal anti-capsular titers. While the anti-MASP-2 mAb did not impair SBA, inhibition of C3 impeded meningococcal killing in most, but not in all sera. These data provide evidence that vaccination can provide protection against invasive meningococcal disease in patients treated with alternative pathway inhibitors
The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels.
No full textSelective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a ~10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs-the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heart-derived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity
Perspectives and Opportunities in Medicinal Chemistry: A View from the Novartis Institute for BioMedical Research in Basel, Switzerland.
No full textAn opinion on changes and opportunities for the pharmaceutical industry in Switzerland, as seen from the Global Discovery Chemistry platform of the Novartis Institutes for BioMedical Research in Basel
CRISPR-Cas9 screen identifies mechanisms of BET bromodomain inhibitor sensitivity including manganese
No full textBET Bromodomain Inhibitors hold promise as therapeutic agents in inflammation and cancer but clinical studies show adverse side-effects at high, sustained dose. Clinical success requires further mechanistic understanding of inhibition of BET bromodomains and biomarkers to optimize efficacious dosing. To uncover the mechanisms of sensitivity and resistance to BETi, we employed a whole-genome CRISPR-Cas9 proliferation screen using colorectal cancer cells. We identify the mTOR signaling pathway as a key determinant of BETi sensitivity and that two Ca/Mn transporters mediate resistance. This later finding led to the discovery that extracellular manganese regulates sensitivity to BETi and that exposure of cells to BETi dose dependently increases intracellular manganese concentration. Our results describe new molecular pathways mediating BETi action and suggest several potential avenues for biomarker discovery
Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug-drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling
No full textRemibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first-pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady-state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27-fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically-based pharmacokinetic (PBPK) model, which well-described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug-drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration-time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks
Machine learning for financial forecasting, planning and analysis: recent developments and pitfalls
No full textThis article is an introduction to machine learning for financial forecasting, planning and analysis (FP&A).Machine learning appears well suited to support FP&A with the highly automated extraction of information from large amounts of data. However, because most traditional machine learning techniques focus on forecasting (prediction), we discuss the particular care that must be taken to avoid the
pitfalls of using them for planning and resource allocation (causal inference). While the naive application of machine learning usually fails in this context, the recently developed double machine learning framework can address causal questions of interest. We review the current literature on machine learning in FP&A and illustrate in a simulation study how machine learning can be used for both forecasting and planning. We also investigate how forecasting and planning improve as the number of data points increases