AREA COVERED: The authors explore the literature to compile the success stories of AI-driven drug candidates that are currently being assessed in clinical trials or have investigational new drug (IND) status. The authors also provide the reader with their expert perspectives for future developments and their opinions on the field.
EXPERT OPINION: Partnerships between AI companies and the pharma industry are booming. The early signs of the impact of AI on DDD are encouraging, and the pharma industry is hoping for breakthroughs. AI can be a promising technology to unveil the greatest successes, but it has yet to be proven as AI is still at the embryonic stage.
Methods: NQC was synthesised and characterised using spectroscopic techniques. The compound was tested for its anti-inflammatory effect using Lipopolysaccharide from Escherichia coli (LPSEc) induced inflammation in mouse macrophages (RAW 264.7 cells). The effect of NQC on inflammatory cytokines was measured using enzyme-linked immune sorbent assay (ELISA). The Nrf2 activity of the compound NQC was determined using 'Keap1:Nrf2 Inhibitor Screening Assay Kit'. To obtain the insights on NQC's activity on Nrf2, molecular docking studies were performed using Schrödinger suite. The metabolic stability of NQC was determined using mouse, rat and human microsomes.
Results: NQC was found to be non-toxic at the dose of 50 µM on RAW 264.7 cells. NQC showed potent anti-inflammatory effect in an in vitro model of LPSEc stimulated murine macrophages (RAW 264.7 cells) with an IC50 value 26.13 ± 1.17 µM. NQC dose-dependently down-regulated the pro-inflammatory cytokines [interleukin (IL)-1β (13.27 ± 2.37 μM), IL-6 (10.13 ± 0.58 μM) and tumor necrosis factor (TNF)-α] (14.41 ± 1.83 μM); and inflammatory mediator, prostaglandin E2 (PGE2) with IC50 values, 15.23 ± 0.91 µM. Molecular docking studies confirmed the favourable binding of NQC at Kelch domain of Keap-1. It disrupts the Nrf2 interaction with kelch domain of keap 1 and its IC50 value was 4.21 ± 0.89 µM. The metabolic stability studies of NQC in human, rat and mouse liver microsomes revealed that it is quite stable with half-life values; 63.30 ± 1.73, 52.23 ± 0.81, 24.55 ± 1.13 min; microsomal intrinsic clearance values; 1.14 ± 0.31, 1.39 ± 0.87 and 2.96 ± 0.34 µL/min/g liver; respectively. It is observed that rat has comparable metabolic profile with human, thus, rat could be used as an in vivo model for prediction of pharmacokinetics and metabolism profiles of NQC in human.
Conclusion: NQC is a new class of NRF2 activator with potent in vitro anti-inflammatory activity and good metabolic stability.
METHODS: Dentin slabs were treated with 0.1% riboflavin-5-phosphate modified (powder added slowly while shaking and then sonicated to enhance the dispersion process) Universal Adhesive Scotch Bond and Zipbond™ along with control (non-modified) and experimental adhesives, photoactivated with blue light for 20s. Hydroxyproline (HYP) release was assessed after 1-week storage. Elastic-modulus testing was evaluated using universal testing machine at 24 h. Resin-dentin interfacial morphology was assessed with scanning electron-microscope, after 6-month storage. 0.1% rhodamine dye was added into each adhesive and analyzed using CLSM. Detection of free amino groups was carried out using ninhydrin and considered directly proportional to optical absorbance. Collagen molecular confirmation was determined using spectropolarimeter to evaluate and assess CD spectra. For molecular docking studies with riboflavin (PDB ID file), the binding pocket was selected with larger SiteScore and DScore using Schrodinger PB software. After curing, Raman shifts in Amide regions were obtained at 8 μm levels. Data were analyzed using Two-way analysis of variance (ANOVA, p ≤ 0.05) and Tukey-Kramer multiple comparison post hoc tests.
RESULTS: At baseline, bond strength reduced significantly (p ≤ 0.05) in control specimens. However, at 6 months' storage, UVA Zipbond™ had significantly higher μTBS. Resin was able to diffuse through the porous demineralized dentin creating adequate hybrid layers in both 0.1%RF modified adhesives in CLSM images. In riboflavin groups, hybrid layer and resin tags were more pronounced. The circular dichroism spectrum showed negative peaks for riboflavin adhesive specimens. Best fitted poses adopted by riboflavin compound are docked with MMP-2 and -9 proteases. Amide bands and CH2 peaks followed the trend of being lowest for control UA Scotch bond adhesive specimens and increasing in Amides, proline, and CH2 intensities in 0.1%RF modified adhesive specimens. All 0.1%RF application groups showed statistically significant (p