scholarly journals Stability of Screening Compounds in Wet DMSO

2008 ◽  
Vol 13 (10) ◽  
pp. 999-1006 ◽  
Author(s):  
Caroline Engeloch ◽  
Ulrich Schopfer ◽  
Ingo Muckenschnabel ◽  
Francois Le Goff ◽  
Hervé Mees ◽  
...  

The impact of storage conditions on compound stability and compound solubility has been debated intensely over the past 5 years. At Novartis, the authors decided to opt for a storage concept that can be considered controversial because they are using a DMSO/water (90/10) mixture as standard solvent. To assess the effect of water in DMSO stocks on compound stability, the authors monitored the purity of a subset of 1404 compounds from ongoing medicinal chemistry projects over several months. The study demonstrated that 85% of the compounds were stable in wet DMSO over a 2-year period at 4 °C. This result validates the storage concept developed at Novartis as a pragmatic approach that takes advantage of the benefits of DMSO/water mixtures while mediating the disadvantages. In addition, the authors describe how purity data collected over the course of the chemical validation of high-throughput screening actives are used to improve the analytical quality of the Novartis screening deck. ( Journal of Biomolecular Screening 2008:999-1006)

2019 ◽  
Vol 26 (13) ◽  
pp. 2330-2355 ◽  
Author(s):  
Anutthaman Parthasarathy ◽  
Sasikala K. Anandamma ◽  
Karunakaran A. Kalesh

Peptide therapeutics has made tremendous progress in the past decade. Many of the inherent weaknesses of peptides which hampered their development as therapeutics are now more or less effectively tackled with recent scientific and technological advancements in integrated drug discovery settings. These include recent developments in synthetic organic chemistry, high-throughput recombinant production strategies, highresolution analytical methods, high-throughput screening options, ingenious drug delivery strategies and novel formulation preparations. Here, we will briefly describe the key methodologies and strategies used in the therapeutic peptide development processes with selected examples of the most recent developments in the field. The aim of this review is to highlight the viable options a medicinal chemist may consider in order to improve a specific pharmacological property of interest in a peptide lead entity and thereby rationally assess the therapeutic potential this class of molecules possesses while they are traditionally (and incorrectly) considered ‘undruggable’.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Marcelo Lopes ◽  
Angelo Karaboyas ◽  
Kazuhiko Tsuruya ◽  
Issa Al Salmi ◽  
Nidhi Sukul ◽  
...  

Abstract Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) has been linked with comorbid conditions, and poorer mental and physical health-related quality-of-life (HR-QOL) in hemodialysis (HD) patients. The Skindex-10 questionnaire and a single itch-related question from the KDQOL-36 have been used to evaluate the impact of pruritus in HD patients. In this analysis, we investigated the performance of the single question and the Skindex-10 as predictors of HR-QOL in HD patients. Method We analyzed data from 4940 HD patients from 17 countries enrolled during year 2 of phase 5 of the Dialysis Outcomes and Practice Patterns Study (DOPPS, 2013): Belgium, Canada, Germany, the Gulf Cooperation Council (GCC) (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates), Italy, Japan, Russia, Spain, Sweden, Turkey, the UK, and the US. The Skindex-10 scores were calculated as per Mathur et al. (2010): responses to each of the 10 questions (0-6 scale), pertaining to how often patients were bothered by itchy skin in the past week, were summed to create a total summary score (range 0-60, with 0 indicating not at all bothered) and 3 subdomain scores [i.e., itching (disease) and its impact on mood/emotional and social functioning]. The itch-related single question from the KDQOL-36 asked: “During the past 4 weeks, to what extent were you bothered by itchy skin?” with response options including “not at all, somewhat, moderately, very much, extremely”. Itch-related measures were collected concurrently with HR-QOL measures: Physical (PCS) and Mental (MCS) Component Summary scores, derived from the SF-12. We calculated the Spearman correlation coefficient between the Skindex-10 (total score and for each of its 3 domains) and the single question. We used separate linear regression models to evaluate the predictive power of 1) the Skindex-10 score, 2) the single itch question, and 3) both, on PCS and MCS outcomes, based on R-squared values. Results Skindex-10 scores varied across countries; the proportion of patients with a very high Skindex-10 score (≥50) ranged from 12% in the GCC to only 2% in Italy, Russia and Sweden. Across all countries, 55% had a Skindex-10 score=0. For the single pruritus question, 37% answered that they were not at all bothered while 16% were very much or extremely bothered by itchy skin. The correlation between the single question and Skindex-10 was 0.71 overall, 0.72 for the disease domain, 0.62 for the social domain, and 0.70 for the emotional domain. Patient characteristics were similar across categories of both pruritus measures. Regression analyses showed that every 10 points higher in the Skindex-10 score was associated with 1.2 point lower PCS (95% CI: -1.4, -0.9) and 1.5 point lower MCS (95% CI: -1.7, -1.3) scores. Similarly, the single question showed increasingly poorer PCS and MCS scores with a greater degree of being bothered by pruritus: compared with patients not at all bothered by itchy skin, patients who were moderately bothered had 4.8 point lower PCS (-5.7, -3.9) and 4.3 point lower MCS (-5.3, -3.3) scores. The R-squared for PCS was 0.065 when using the single question and only 0.033 when using the Skindex-10 as the predictor. R-squared was also higher for MCS when using the single question (0.056) vs. Skindex-10 (0.052). When including both pruritus measures, the predictive power for PCS did not improve compared to the single question (R2=0.065), while increasing only slightly (R2=0.063) for MCS. Conclusion The single KDQOL-36 question about the extent bothered by itchy skin over the past 4 weeks was highly correlated with the Skindex-10 score and at least as predictive – if not more – of key HR-QOL measures as the Skindex-10. In daily clinical practice, utilizing 1 simple question about the extent patients are bothered by itchy skin can be a feasible and efficient way for routine assessment of pruritus to better identify HD patients with not only CKD-aP but also poorer HR-QoL.


2005 ◽  
Vol 15 (S1) ◽  
pp. 174-178 ◽  
Author(s):  
Kathleen Mussatto ◽  
James Tweddell

The past two decades have witnessed a major shift towards repair of most congenital cardiac malformations during the neonatal or infant periods of life.1 Early anatomic correction or palliation, dramatic improvements in survival, and reduced morbidity due to improvements in perioperative and long-term medical management, have resulted in new populations of children that have reaped the benefits of the best care currently available for treatment of congenital cardiac disease. The impact of the congenital cardiac malformations, however, extends far beyond the walls of the hospital or clinic where we diagnose, treat, and follow our patients. The breakthrough of achieving predictable results with repair or palliation of most lesions during the neonatal and infant periods mandates us to look beyond survival, and to examine the lives our patients lead when they are outside of our care. Our purpose in this review is to discuss the measures of psychosocial outcome that are appropriate for exploration in those neonates and infants who survive cardiac surgery, to explore what is known about the psychosocial outcomes and quality of life for these patients, and what needs exist for future research.


1975 ◽  
Vol 16 (2) ◽  
pp. 285-301 ◽  
Author(s):  
David Henige

This paper argues that interpretations which would view pre-colonial Akan political life as ‘normative’ and structured may be incorrect, at least in so far as stool succession is concerned. Contemporaneous evidence for this early period is at best sparse and at worst simply non-existent and seldom allows even tentative hypotheses. Rather, it is necessary to infer past practices from more recent data, whether this be observation of present behaviour or recent testimony about the past. In this case I have used the testimony presented at various stool and jurisdictional disputes during the colonial period for which records survive. These are generally, of course, ex parte statements and can be used only with caution. However, there is a surprising consensus throughout these records that both the principles and the patterns of stool succession and paramountcy in the pre-colonial period were variegated and even extemporaneous although, not surprisingly, there is much dispute about the reasons for this. On balance, this testimony suggests that a re-interpretation of early Akan political culture using a wider range of evidence is desirable.Although this implies that the impact of colonial ‘indirect’ rule was not as profound as has often been supposed, I have not discussed this problem directly except as it bears on the quality of the data. Nor have I attempted to analyse the day-to-day dynamics of political life, either for the earlier period (which would be impossible on the evidence) or for the colonial period (which would be irrelevant for comparison). Nevertheless, within the restricted compass of stool succession and paramountcy the argument here is that colonial rule involved little fundamental change from earlier practices. If anything, it probably served to delimit a greater range of previous options by seeking to codify them.


2015 ◽  
Vol 7 (14) ◽  
pp. 1847-1852 ◽  
Author(s):  
Philip Jones ◽  
Stuart McElroy ◽  
Angus Morrison ◽  
Andrew Pannifer

2011 ◽  
Vol 16 (9) ◽  
pp. 1007-1017 ◽  
Author(s):  
Joost C. M. Uitdehaag ◽  
Cecile M. Sünnen ◽  
Antoon M. van Doornmalen ◽  
Nikki de Rouw ◽  
Arthur Oubrie ◽  
...  

Over the past years, improvements in high-throughput screening (HTS) technology and compound libraries have resulted in a dramatic increase in the amounts of good-quality screening hits, and there is a growing need for follow-on hit profiling assays with medium throughput to further triage hits. Here the authors present such assays for the colony-stimulating factor 1 receptor (CSF1R, Fms), including tests for cellular activity and a homogeneous assay to measure affinity for inactive CSF1R. They also present a high-throughput assay to measure target residence time, which is based on competitive binding kinetics. To better fit koff rates, they present a modified mathematical model for competitive kinetics. In all assays, they profiled eight reference inhibitors (imatinib, sorafenib, sunitinib, tandutinib, dasatinib, GW2580, Ki20227, and J&J’s pyrido[2,3-d]pyrimidin-5-one). Using the known biochemical selectivities of these inhibitors, which can be quantified using metrics such as the selectivity entropy, the authors have determined which assay readout best predicts hit selectivity. Their profiling shows surprisingly that imatinib has a preference for the active form of CSF1R and that Ki20227 has an unusually slow target dissociation rate. This confirms that follow-on hit profiling is essential to ensure that the best hits are selected for lead optimization.


2013 ◽  
Vol 66 (12) ◽  
pp. 1483 ◽  
Author(s):  
Jonathan B. Baell ◽  
Lori Ferrins ◽  
Hendrik Falk ◽  
George Nikolakopoulos

Pan assay interference compounds (PAINS) are readily discovered in any bioassay and can appear to give selective and optimisable hits. The most common PAINS can be readily recognised by their structure. However, there are compounds that closely resemble PAINS that are not specifically recognised by the PAINS filters. In addition, highly reactive compounds are not encoded for in the PAINS filters because they were excluded from the high-throughput screening (HTS) library used to develop the filters and so were never present to provide indicting data. A compounding complication in the area is that very occasionally a PAINS compound may serve as a viable starting point for progression. Despite such an occasional example, the literature is littered with an overwhelming number of examples of compounds that fail to progress and were probably not optimisable in the first place, nor useful tool compounds. Thus it is with great caution and diligence that compounds possessing a known PAINS core should be progressed through to medicinal chemistry optimisation, if at all, as the chances are very high that the hits will be found to be non-progressable, often after a significant waste of resources.


2000 ◽  
Vol 5 (5) ◽  
pp. 297-306 ◽  
Author(s):  
John C. Owicki

Fluorescence polarization and anisotropy are two nearly equivalent techniques that have together, over the past 5 years, achieved wide use in high throughput screening in drug discovery. These are single-label methods that can be used to construct homogeneous assays that are fast, sensitive, and resistant to some significant interferences. Moreover, the assays are relatively inexpensive. This review surveys the peer-reviewed literature on the subject and explores some of the fundamental issues that bear on assay performance.


2021 ◽  
Vol 27 ◽  
pp. 107602962110408
Author(s):  
Naser Al-Husban ◽  
Leena N. Alnsour ◽  
Zaid El-adwan ◽  
Nada A. Saleh ◽  
Mazen El-Zibdeh

Background: During pregnancy, the risk of venous thrombo-embolism (VTE) is increased at least five times compared with non-pregnant women of the same age, while the relative risk in the postpartum period can be as high as sixty times. The aim of the study was to explore the impact of pregnancy-related VTE on patients' mental, professional, social and personal life. Methods and Materials: Cross-sectional study at Jordan University Hospital's Obstetrics Department. Results: There were 112 women. Forty-six (41.1%) had a postpartum VTE. Twenty-eight of the patients (25%) had comorbidity. Eleven (9.9%) had a previous episode of VTE. Thirty-nine (35%) of the women reported three or more hospital visits over the past six months. Twenty-one (19.6%) of the women answered that their leg or chest pain has impeded their social activities. Anxiety/Depression was reported by 96.43% while Pain/Discomfort by 73.21%. A significant reduction of time spent on their work (correlation = 0.663, significant at <0.01) and accomplishing less work (correlation = 0.787, this was significant at <0.01) was found; 57.14% of patients indicated that VTE affecting their future pregnancies; 58.9% of patients were receiving anticoagulants with the most commonly used drug was aspirin. Twenty-four (36.4%) of the women were on multiple anticoagulant therapies. Twenty-five of the patients receiving medications do not monitor their medications and 20 patients said that monitoring the drug level was a bother to them. Conclusions: Pregnancy-related VTE had a significant adverse impact on physical, mental and professional life of women. It also had negative effects on future pregnancy plans.


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