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.
MATERIALS AND METHODS: In silico Molecular Dynamics (MD) was used to determine the interactions of K21 inside the pocket of the targeted protein (crystal structure of fibroblast collagenase-1 complexed to a diphenyl-ether sulphone based hydroxamic acid; PDB ID: 966C; Crystal structure of MMP-2 active site mutant in complex with APP-derived decapeptide inhibitor. MD simulations were accomplished with the Desmond package in Schrödinger Drug Discovery Suite. Blood samples (~ 0.5 mL) collected into K2EDTA were immediately transferred for further processing using the Litron MicroFlow® PLUS micronucleus analysis kit for mouse blood according to the manufacturer's instructions. Bacterial Reverse Mutation Test of K21 Molecule was performed to evaluate K21 and any possible metabolites for their potential to induce point mutations in amino acid-requiring strains of Escherichia coli (E. coli) (WP2 uvrA (tryptophan-deficient)).
RESULTS: Molecular Simulation depicted that K21 has a specific pocket binding on various MMPs and SrtA surfaces producing a classical clouting effect. K21 did not induce micronuclei, which are the result of chromosomal damage or damage to the mitotic apparatus, in the peripheral blood reticulocytes of male and female CD-1 mice when administered by oral gavage up to the maximum recommended dose of 2000 mg/kg. The test item, K21, was not mutagenic to Salmonella typhimurium (S. typhimurium) strains TA98, TA100, TA1535 and TA1537 and E. coli strain WP2 uvrA in the absence and presence of metabolic activation when tested up to the limit of cytotoxicity or solubility under the conditions of the test.
CONCLUSION: K21 could serve as a potent protease inhibitor maintaining the physical and biochemical properties of dental structures.
METHODS: Experimental adhesives modified with different fractions of dioctadecyldimethyl ammonium bromide quaternary ammonium and riboflavin (QARF) were formulated. Dentine specimens were bonded to resincomposites with control or the experimental adhesives to be evaluated for bond strength, interfacial morphology, micro-Raman analysis, nano-CT and nano-leakage expression. In addition, the antibacterial and biocompatibilities of the experimental adhesives were investigated. The endogenous proteases activities and their molecular binding-sites were studied.
RESULTS: Modifying the experimental adhesives with QARF did not adversely affect micro-tensile bond strength or the degree of conversion along with the demonstration of anti-proteases and antibacterial abilities with acceptable biocompatibilities. In general, all experimental adhesives demonstrated favourable bond strength with increased and improved values in 1% QARF adhesive at 24 h (39.2 ± 3.0 MPa) and following thermocycling (34.8 ± 4.3 MPa).
SIGNIFICANCE: It is possible to conclude that the use of QARF with defined concentration can maintain bond strength values when an appropriate protocol is used and have contributed in ensuring a significant decrease in microbial growth of biofilms. Incorporation of 1% QARF in the experimental adhesive lead to simultaneous antimicrobial and anti-proteolytic effects with low cytotoxic effects, acceptable bond strength and interfacial morphology.
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.