5 research outputs found
Identification and characterization of novel indole based small molecules as anticancer agents through SIRT1 inhibition
In our pursuit to develop new potential anticancer leads, we designed a combination of structural units of indole and substituted triazole; and a library of 1-{1-methyl-2-4-phenyl-5-(propan-2-ylsulfanyl)-4H-1,2,4-triazol-3-yl ]-1H-indol-3-yl}methanamine derivatives was synthesized and characterized. Cytotoxic evaluations of these molecules over a panel of three human cancer cell lines were carried out. Few molecules exhibited potent growth inhibitory action against the treated cancer cell lines at lower micro molar concentration. An in vitro assay investigation of these active compounds using recombinant human SIRT1 enzyme showed that one of the compounds (IT-14) inhibited the deacetylation activity of the enzyme. The in vivo study of IT-14 exemplified its promising action by reducing the prostate weight to the body weight ratio in prostate hyperplasia animal models. A remarkable decrease in the disruption of histoarchitecture of the prostate tissues isolated from IT-14 treated animal compared to that of the positive control was observed. The molecular interactions with SIRT1 enzyme were also supported by molecular docking simulations. Hence this compound can act as a lead molecule to treat prostatic hyperplasia. (C) 2013 Elsevier Masson SAS. All rights reserved
Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1)
Silent
mating-type information regulation 2 homologue 1 (SIRT1),
being the homologous enzyme of silent information regulator-2 gene
in yeast, has multifaceted functions. It deacetylates a wide range
of histone and nonhistone proteins; hence, it has good therapeutic
importance. SIRT1 was believed to be overexpressed in many cancers
(prostate, colon) and inflammatory disorders (rheumatoid arthritis).
Hence, designing inhibitors against SIRT1 could be considered valuable.
Both structure-based and ligand-based drug design strategies were
employed to design novel inhibitors utilizing high-throughput virtual
screening of chemical databases. An energy-based pharmacophore was
generated using the crystal structure of SIRT1 bound with a small
molecule inhibitor and compared with a ligand-based pharmacophore
model that showed four similar features. A three-dimensional quantitative
structure–activity relationship (3D-QSAR) model was developed
and validated to be employed in the virtual screening protocol. Among
the designed compounds, <b>Lead 17</b> emerged as a promising
SIRT1 inhibitor with IC<sub>50</sub> of 4.34 μM and, at nanomolar
concentration (360 nM), attenuated the proliferation of prostate cancer
cells (LnCAP). In addition, <b>Lead 17</b> significantly reduced
production of reactive oxygen species, thereby reducing pro inflammatory
cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory
potential of the compound was ascertained using an animal paw inflammation
model induced by carrageenan. Thus, the identified SIRT1 inhibitors
could be considered as potent leads to treat both cancer and inflammation
Development of novel N-linked aminopiperidine-based mycobacterial DNA gyrase B inhibitors: Scaffold hopping from known antibacterial leads
Advances in Animal Models and Cutting-Edge Research in Alternatives: Proceedings of the Third International Conference on 3Rs Research and Progress, Vishakhapatnam, 2022.
Animal experimentation has been integral to drug discovery and development and safety assessment for many years, since it provides insights into the mechanisms of drug efficacy and toxicity (e.g. pharmacology, pharmacokinetics and pharmacodynamics). However, due to species differences in physiology, metabolism and sensitivity to drugs, the animal models can often fail to replicate the effects of drugs and chemicals in human patients, workers and consumers. Researchers across the globe are increasingly applying the Three Rs principles by employing innovative methods in research and testing. The Three Rs concept focuses on: the replacement of animal models (e.g. with in vitro and in silico models or human studies), on the reduction of the number of animals required to achieve research objectives, and on the refinement of existing experimental practices (e.g. eliminating distress and enhancing animal wellbeing). For the last two years, Oncoseek Bio-Acasta Health, a 3-D cell culture-based cutting-edge translational biotechnology company, has organised an annual International Conference on 3Rs Research and Progress. This series of global conferences aims to bring together researchers with diverse expertise and interests, and provides a platform where they can share and discuss their research to promote practices according to the Three Rs principles. In November 2022, the 3rd international conference, Advances in Animal Models and Cutting-Edge Research in Al- ternatives, took place at the GITAM University in Vishakhapatnam (AP, India) in a hybrid format (i.e. online and in- person). These conference proceedings provide details of the presentations, which were categorised under five different topic sessions. It also describes a special interactive session on in silico strategies for preclinical research in oncology, which was held at the end of the first day