Assessment of structural and activity-related contributions of various PIM-1 kinase inhibitors in the treatment of leukemia and prostate cancer.

One of the most perilous illnesses in the world is cancer. The cancer may be associated with the mutation of different genes inside the body. The PIM kinase, also known as the serine/threonine kinase, plays a critical role in the biology of different kinds of cancer. They are widely distributed and associated with several biological processes, including cell division, proliferation, and death. Aberration of PIM-1 kinase is found in varieties of cancer. Prostate cancer and leukemia can both be effectively treated with PIM-1 kinase inhibitors. There are several potent compounds that have been explored in this review based on heterocyclic compounds for the treatment of prostate cancer and leukemia that have strong effects on the suppression of PIM-1 kinase. The present review summarizes the PIM-1 kinase pathway, their inhibitors under clinical trial, related patents, and SAR studies of several monocyclic, bicyclic, and polycyclic compounds. The study related to their molecular interactions with receptors is also included in the present manuscript. The study may be beneficial to scientists for the development of novel compounds as PIM-1 inhibitors in the treatment of prostate cancer and leukemia.

Integrated fragment-based drug design and virtual screening techniques for exploring the antidiabetic potential of thiazolidine-2,4-diones: Design, synthesis and in vivo studies.

Diabetes mellitus is a metabolic disorder characterized by elevated blood sugar levels and related complications. This study focuses on harnessing and integrating fragment-based drug design and virtual screening techniques to explore the antidiabetic potential of newly synthesized thiazolidine-2,4-dione derivatives. The research involves the design of novel variations of thiazolidine-2,4-dione compounds by Fragment-Based Drug Design. The screening process involves pharmacophore based virtual screening through docking algorithms, and the identification of newly twelve top-scoring compounds. The molecular docking analysis revealed that compounds SP4e, SP4f showed highest docking scores of -9.082 and -10.345. The binding free energies of the compounds SP4e, SP4f and pioglitazone was found to be -19.9, -16.1 and -13 respectively, calculated using the Prime MM/GBSA approach. The molecular dynamic study validates the docking results. Furthermore, In the Swiss albino mice model, both SP4e and SP4f exhibited significant hypoglycaemic effects, comparable to the reference drug pioglitazone. Furthermore, these compounds demonstrated favorable effects on the lipid profile, reducing total cholesterol, triglycerides, and LDL levels while increasing HDL levels. In mice tissue, the disease control group showed PPAR-γ expression of 4.200 ± 0.24, while compound SP4f displayed higher activation at 7.84 ± 0.431 compared to compound SP4e with an activation of 7.68 ± 0.65. In zebrafish model, SP4e and SP4f showed significant reductions in blood glucose levels and lipid peroxidation, along with increased glutathione levels and catalase activity. These findings highlighted the potential of SP4e and SP4f as antidiabetic agents, warranting further exploration for therapeutic applications. The in vitro study was performed in HEK-2 cell line, the pioglitazone group demonstrated PPAR-γ expression of EC50 = 575.2, while compound SP4f exhibited enhanced activation at EC50 = 739.0 in contrast to compound SP4e activation of EC50 = 826.7.

Recent updates on structural insights of MAO-B inhibitors: a review on target-based approach.

Parkinson's disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain's substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson's disease may be happened because of various genetic and environmental factors. Parkinson's disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al. reported MAO-B inhibitors with IC50 0.0051 µM and showed good binding affinity. Enriquez et al. reported a compound with IC50 144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure-activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.