An Analysis of Different Components of a High-Throughput Screening Library.

Since many projects at pharmaceutical organizations get their start from a high-throughput screening (HTS) campaign, improving the quality of the HTS deck can improve the likelihood of discovering a high-quality lead molecule that can be progressed to a drug candidate. Over the past decade, Janssen has implemented several strategies for external compound acquisition to augment the screening deck beyond the chemical space and number of molecules synthesized for internal projects. In this report, we analyzed the performance of each of those compound collections in the screening campaigns performed internally within Janssen during the last five years. We classified the screening library into two broad categories: Internal and External. The comparison of the performance of these sets of libraries was done by considering the primary, confirmation, and dose response hit rates. Our analysis revealed that Internal compounds (resulting from numerous medicinal chemistry efforts against diverse protein targets) have higher average confirmation hit rates than External ones; however, actives from both categories show similar probabilities of hitting multiple distinct targets. We also investigated the property landscape of both sets of libraries to identify the key elements which make a difference in these categories of compounds. From this analysis, Janssen aims to understand the descriptor landscape of the compounds with the highest hit rates and to use them for improving its future acquisition strategies as well as to inform our plating strategy.

Effective management of Colles fracture using Murivenna and Abha Guggulu - A case report.

Colles fracture is the commonest fracture encountered in orthopedic practice that demands prompt therapeutic intervention, and adequate follow-up to ensure complete healing. Various types of fractures, methods of reduction, and healing have been explained in the classical Ayurveda texts. These techniques are scientific and time-tested. This paper aims to report the successful management of Colles fracture case using Ayurveda and modern techniques with the use of Murivenna (an oil-based herbal formulation mentioned in the contemporary texts of Ayurveda), half-cast POP, and aluminum splinted bandage along with the internal medicine AbhaGuggulu. A 75-year-old moderately built woman diagnosed with Colles fracture was treated with a closed manipulative reduction technique followed by a below-elbow half-cast POP and an aluminum splint. Murivenna was poured anteriorly to the fractured site and Abha Guggulu was administered internally. Re-bandaging was done on the 7th day and 21st day. The bandage was removed on the 35th day. The patient's condition improved considerably with a good range of wrist movements and then she was advised to commence rehabilitation. This integrative method, adhering to Ayurvedic principles and modern techniques is unique, patient-friendly, and without adverse events.

Optimization of a High-Throughput Cell-Based Screening Strategy to Identify Small-Molecule Inhibitors of IL-23 Signaling.

Interleukin-23 (IL-23) is a key cytokine implicated in the pathogenesis of autoimmune disorders, including psoriasis and ulcerative colitis. Although targeted IL-23 antibody therapeutics are used clinically, there are no small-molecule therapeutics that selectively inhibit IL-23 signaling. To address this gap, we developed a high-throughput screening strategy employing an IL-23-responsive cell-based luciferase reporter gene assay as the primary screen, with cellular cytotoxicity and off-target counter screening assays to identify IL-23 pathway-specific inhibitors. The primary screening assay utilized avian DT40 cells, genetically engineered to overexpress IL-23R, IL-12Rß1, STAT5, and firefly luciferase, in a 1536-well format. Treatment of these cells with IL-23 resulted in the phosphorylation and activation of STAT5, which was completely inhibited by the pan-JAK inhibitor tofacitinib. Assay performance was robust, with signal-to-background >7-fold and Z' > 0.5 over 40 screening plates (approximately 24,000 compounds), with a hit rate of 5% (>66.9% activity cutoff). Of these 1288 hits, 66% were identified as cytotoxic by incubating the IL-23 reporter cells with compound overnight and measuring cell viability. Further assessment of specificity via examination of impact on off-target IFN-γ signaling eliminated an additional 230 compounds, leaving 209 that were evaluated for dose-response activity. Of these compounds, 24 exhibited IC50 values of <7 µM and ≥80% inhibition of IL-23 activity, with >3-fold selectivity over IFN-γ inhibition, thus representing promising starting points for prospective IL-23 pathway small-molecule inhibitors.