Beyond peptides: Unveiling the design strategies, structure activity correlations and protein-ligand interactions of small molecule inhibitors against PD-1/PD-L1.

The landscape of cancer treatment has been transformed by the emergence of immunotherapy, especially through the use of antibodies that target the PD-1/PD-L1 pathway. Recently, there has been a notable increase in interest surrounding immune checkpoint inhibitors for cancer therapy. While antibody-based approaches have drawbacks like high costs and prolonged activity, the approval of monoclonal antibodies such as pembrolizumab and nivolumab has paved the way for a range of alternative therapies, including peptides, peptidomimetics, and small-molecule inhibitors.

Expression of PPAR-γ TF by newly synthesized thiazolidine-2,4-diones to manage glycemic control: Insights from in silico, in vitro and experimental pharmacology in wistar rats.

In pursuit of novel antidiabetic agents to combat type II diabetes mellitus, our study focused on identifying pharmacophoric features responsible for PPAR-γ expression, a key regulator of glucose homeostasis and lipid metabolism. This goal was achieved through pharmacophore model generation and screening of rationally designed library of thiazolidine-2,4-dione hybrids (7a-7f). The top hits were synthesized, characterized, and evaluated for their in vitro and in vivo antidiabetic activities.

Novel PPAR-γ agonists as potential neuroprotective agents against Alzheimer's disease: rational design, synthesis evaluation, PPAR-γ binding assay and transactivation and expression studies.

Alzheimer's disease (AD) is a neurological disorder. It is caused by accumulation of amyloid beta (Aβ) plaques and tau tangles, which gradually leads to cognitive decline and memory loss. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor, plays a significant role in regulating genes responsible for metabolism and inflammation.

Development of novel thiazolidine-2,4-dione derivatives as PPAR-γ agonists through design, synthesis, computational docking, MD simulation, and comprehensive and evaluation.

The present study was conducted to develop new novel 2,4-thiazolidinedione derivatives (3h-3j) as peroxisome proliferator-activated receptor-γ (PPAR-γ) modulators for antidiabetic activity. The objective was to overcome the adverse effects of existing thiazolidinediones while maintaining their pharmacological benefits. The synthesized compounds were elucidated based on FT-IR, H-NMR, C-NMR, and MS techniques.

Novel Derivatives of Eugenol as a New Class of PPARγ Agonists in Treating Inflammation: Design, Synthesis, SAR Analysis and In Vitro Anti-Inflammatory Activity.

The main objective of this research was to develop novel compounds from readily accessed natural products especially eugenol with potential biological activity. Eugenol, the principal chemical constituent of clove () from the family Myrtaceae is renowned for its pharmacological properties, which include analgesic, antidiabetic, antioxidant, anticancer, and anti-inflammatory effects. According to reports, PPARγ regulates inflammatory reactions.

Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects.

Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention.

Biphenyl-based small molecule inhibitors: Novel cancer immunotherapeutic agents targeting PD-1/PD-L1 interaction.

The immune checkpoint proteins are those key to the body's immunity which can either boost the immune system to protect the body from pathogens; or suppress the body's immunity system for the goal of self-tolerance. Cancer cells have evolved some mechanisms to boost the immuno-inhibitory checkpoints to bypass the immune system of the body. The binding of Programmed Cell Death-1 (PD-1) protein with its ligand Programmed Cell Death Ligand-1 (PD-L1) promotes this kind of immune-inhibitory signal.

Novel derivatives of eugenol as potent anti-inflammatory agents PPARγ agonism: rational design, synthesis, analysis, PPARγ protein binding assay and computational studies.

Eugenol is a natural product abundantly found in clove buds known for its pharmacological activities such as anti-inflammatory, antidiabetic, antioxidant, and anticancer activities. It is well known from the literature that peroxisome proliferator-activated receptors (PPARγ) have been reported to regulate inflammatory responses. In this backdrop, we rationally designed semi-synthetic derivatives of eugenol with the aid of computational studies, and synthesized, purified, and analyzed four eugenol derivatives as PPARγ agonists.

A promising in silico protocol to develop novel PPARγ antagonists as potential anticancer agents: Design, synthesis and experimental validation via PPARγ protein activity and competitive binding assay.

Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor superfamily is an excellent example of targets that orchestrates cancer, inflammation, lipid and glucose metabolism. We report a protocol for the development of novel PPARγ antagonists by employing 3D QSAR based virtual screening for the identification of ligands with anticancer properties. The models are generated based on a large and diverse set of PPARγ antagonist ligands by the HYPOGEN algorithm using Discovery Studio 2019 drug design software.

Design, parallel synthesis of Biginelli 1,4-dihydropyrimidines using PTSA as a catalyst, evaluation of anticancer activity and structure activity relationships via 3D QSAR studies.

Biginelli 1,4-dihydropyrimidines are extensively screened for their potential anticancer activity in the last decade. In this context, a series of Biginelli 1,4-dihydropyrimidines were designed and synthesised using PTSA as an efficient catalyst. The synthesised 1,4-dihydropyrimidines were screened for their anticancer activity against MCF-7 breast cancer cells by measuring cytotoxicity.

Two Rationally Identified Novel Glitazones Reversed the Behavioral Dysfunctions and Exhibited Neuroprotection Through Ameliorating Brain Cytokines and Oxy-Radicals in ICV-LPS Neuroinflammatory Rat Model.

The present study has planned to evaluate the neuroprotective activity of two novel glitazones in a neuroinflammatory rat model. Two novel glitazones were selected from an in-house virtual library of glitazones based on their docking scores against peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein and other parameters studied in computational studies. Initially, an acute oral toxicity study was carried out for glitazones in rats to assess the toxicity profile and to determine the therapeutic range for neuroprotective evaluation.

Minutes of PPAR-γ agonism and neuroprotection.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) is one of the ligand-activated transcription factors which regulates a number of central events and considered as a promising target for various neurodegenerative disease conditions. Numerous reports implicate that PPAR-γ agonists have shown neuroprotective effects by regulating genes transcription associated with the pathogenesis of neurodegeneration. In regards, this review critically appraises the recent knowledge of PPAR-γ receptors in neuroprotection in order to hypothesize potential neuroprotective mechanism of PPAR-γ agonism in chronic neurological conditions.

Development of Novel Rhodanine Analogs as Anticancer Agents: Design, Synthesis, Evaluation and CoMSIA Study.

Background: A series of novel 5-substituted benzylidene rhodanine derivatives using four different amines were designed based on our previously developed CoMSIA (Comparative molecular similarity indices analysis) model for the anticancer activity.

Methods: The designed rhodanines were synthesized via dithiocarbamate formation, cyclization and Knoevenagel condensation. The structures of the synthesized compounds were confirmed and analyzed by spectral studies.

Rational Design, Synthesis, and In Vitro Neuroprotective Evaluation of Novel Glitazones for PGC-1α Activation via PPAR-γ: a New Therapeutic Strategy for Neurodegenerative Disorders.

In the present study, two structurally diverse novel glitazones were designed and synthesized for activation of central PGC-1α signaling through stimulation of PPAR-γ receptor. The functional interaction between PGC-1α and PPAR-γ is a key interaction in the normal physiology of neuroprotective mechanism. Therefore, activation of PPAR-γ-dependent PGC-1α co-activator signaling could be an effective strategy to exhibit neuroprotection in several neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and cerebral ischemia.

Structure-based design and synthesis of new 4-methylcoumarin-based lignans as pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) inhibitors.

Suppression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) along with nitric oxide reduction in RAW 264.7 cells by 7,8-dihydroxy-4-methylcoumarin, ethyl p-coumarate, ethyl caffeate and ethyl ferulate drove us to search structural-analogues of the aforementioned compounds through structure-based drug design. Docking studies revealed that substituted cinnamic acids and their ethyl esters (2-7c) showed higher GoldScore-fitness (GSF) and non-bonding interactions with target proteins than 7,8-dihydroxy-4-methylcoumarin (1a) and 7,8-dihydroxy-5-methylcoumarin (1b).

Thiazolidinediones as antidiabetic agents: A critical review.

Thiazolidinediones (TZDs) or Glitazones are an important class of insulin sensitizers used in the treatment of Type 2 diabetes mellitus (T2DM). TZDs were reported for their antidiabetic effect through antihyperglycemic, hypoglycemic and hypolipidemic agents. In time, these drugs were known to act by increasing the transactivation activity of Peroxisome Proliferators Activated Receptors (PPARs).

Design, synthesis and glucose uptake activity of some novel glitazones.

Herein, we report a library consisting of some novel glitazones containing thiazolidinedione and its bioisosteres, rhodanine and oxadiazolidine ring structures as their basic scaffold for their antidiabetic activity. Twelve novel glitazones with diverse chemical structures were designed and synthesized by adopting appropriate synthetic schemes and analyzed. Later, subjected to in vitro glucose uptake assay in the absence and presence of insulin to confirm their antidiabetic activity using rat hemi-diaphragm.

Discovery of novel glitazones incorporated with phenylalanine and tyrosine: synthesis, antidiabetic activity and structure-activity relationships.

We report a series of new glitazones incorporated with phenylalanine and tyrosine. All the compounds were tested for their in vitro glucose uptake activity using rat-hemidiaphragm, both in presence and absence of insulin. Six of the most active compounds from the in vitro screening were taken forward for their in vivo triglyceride and glucose lowering activity against dexamethazone induced hyperlipidemia and insulin resistance in Wistar rats.

Novel Biginelli dihydropyrimidines with potential anticancer activity: a parallel synthesis and CoMSIA study.

Novel Biginelli dihydropyrimidines of biological interest were prepared using p-toluene sulphonic acid as an efficient catalyst. All the thirty-two synthesised dihydropyrimidines were evaluated for their in vitro antioxidant activity using DPPH method. Only, compounds 28 and 29 exhibited reasonably good antioxidant activity.

QSAR Study on Thiazolidine-2,4-dione Derivatives for Antihyperglycemic Activity.

A set of seventy four molecules belonging to the class of thioglitazones were subjected to the QSAR analysis for their antihyperglycemic activity. All the molecules were subjected to energy minimization to get 3D structures, followed by conformational analysis to get the conformation of the molecule associated with the least energy and highest stability. Various physico-chemical parameters were then calculated using ALCHEMY 2000 software, namely, thermodynamic parameters, structure-dependant parameters, topological parameters and charge-dependant parameters.

Predicting anti-HIV activity of 1,3,4-thiazolidinone derivatives: 3D-QSAR approach.

HIV-1 (human immunodeficiency virus type-1) is the pathogenic retrovirus and causative agent of AIDS. HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as NNRTIs and NRTIs.