Novel dihydropyrimidines as promising EGFR & HER2 inhibitors: Insights from experimental and computational studies.

Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.

Anticancer potential of novel symmetrical and asymmetrical dihydropyridines against breast cancer via EGFR inhibition: molecular design, synthesis, analysis and screening.

A series of novel symmetrical and asymmetrical dihydropyridines (HD 1-15) were designed, subjected to in silico ADMET prediction, synthesized, analyzed by IR, NMR, Mass analytical techniques and evaluated against epidermal growth factor receptor (EGFR) as inhibitors against Breast cancer. The results of predicted ADMET studies demonstrated the drug-likeness properties of the reported compounds. The in vitro cytotoxicity assessment of the synthesized compounds revealed that all of them showed good activity (IC50 ranging from 16.75 to 66.54 µM) towards MCF-7 breast cancer cells compared to the standard drug, Lapatinib (IC50 = 2.02 µM). Among these, compounds HD-6, HD-7, and HD-8 displayed the most potent activity with IC50 value of 21.26, 16.75, and 18.33 µM, respectively. Cytotoxicity of all compounds was tested on normal vero cells for comparison at different concentrations using the MTT assay. In addition to the MTT assay, the potent dihydropyridines derivatives were screened for EGFRwt kinase inhibition assay at concentrations ranging from 1 nM to 360 nM. Among the three compounds tested, HD-8 showed reasonably good inhibition with an IC50 value of 15.90 ± 1.20 nM compared to a standard Lapatinib IC50 value of 10.28 ± 1.01 nM. Based on the molecular docking study against EGFR, the most active derivatives HD-7 and HD-8 were docked against the active site of the protein and showed better binding affinity than the standard lapatinib. Additionally, molecular dynamics (MD) simulations were performed to explore the stability of the protein-ligand complex, its dynamic behavior, and the binding affinity.

Development of novel thiazolidine-2,4-dione derivatives as PPAR-γ agonists through design, synthesis, computational docking, MD simulation, and comprehensive in vitro and in vivo 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, 1H-NMR, 13C-NMR, and MS techniques. Molecular docking was utilized to investigate the interaction binding modes, binding free energy, and amino acids engaged in the compounds' interactions with the target protein. Subsequently, molecular dynamics modelling was used to assess the stability of the top-docked complexes and an assay was utilized to assess the cytotoxicity of the compounds to C2C12 myoblasts. Compounds 3h-3j exhibited PPAR-γ modulatory activity and demonstrated significant hypoglycaemic effects when compared to the reference drug pioglitazone. The new compounds were evaluated for their in vivo blood glucose-lowering potential by using a dexamethasone-induced diabetic rat model. All the compounds showed a hypoglycaemic effect of 108.04 ± 4.39, 112.55 ± 6.10, and 117.48 ± 43.93, respectively, along with pioglitazone (153.93 ± 4.61) compared to the diabetic control. Additionally, all the compounds significantly reduced AST and ALT levels and did not cause liver damage.

Isolation, Identification, and Antibacterial Properties of Prodigiosin, a Bioactive Product Produced by a New Serratia marcescens JSSCPM1 Strain: Exploring the Biosynthetic Gene Clusters of Serratia Species for Biological Applications.

Prodigiosin pigment has high medicinal value, so exploring this compound is a top priority. This report presents a prodigiosin bioactive compound isolated from Serratia marcescens JSSCPM1, a new strain. The purification process of this compound involves the application of different chromatographic methods, including UV-visible spectroscopy, high-performance liquid chromatography (HPLC), and liquid chromatography-mass spectrometry (LC/MS). Subsequent analysis was performed using nuclear magnetic resonance (NMR) to achieve a deeper understanding of the compound's structure. Finally, through a comprehensive review of the existing literature, the structural composition of the isolated bioactive compound was found to correspond to that of the well-known compound prodigiosin. The isolated prodigiosin compound was screened for antibacterial activity against both Gram-positive and Gram-negative bacteria. The compound inhibited the growth of Gram-negative bacterial strains compared with Gram-positive bacterial strains. It showed a maximum minimum inhibitory concentration against Escherichia coli NCIM 2065 at a 15.9 ± 0.31 µg/mL concentration. The potential binding capabilities between prodigiosin and the OmpF porin proteins (4GCS, 4GCP, and 4GCQ) were determined using in silico studies, which are generally the primary targets of different antibiotics. Comparative molecular docking analysis indicated that prodigiosin exhibits a good binding affinity toward these selected drug targets.

Association between severe retinopathy of prematurity (ROP) and poor motor neurodevelopmental outcome.

During the final (third) trimester outside of the womb, the retina develops significantly and is vulnerable to problems. Similar to how the cerebral cortex does, the cerebellum also grows quickly during this time and is susceptible to upsetting environmental influences. The only factors that show promise for lowering the incidence and retinopathy of prematurity (ROP) severity among high-risk infants are prematurity prevention, preeclampsia control, and prudent use of oxygen therapy and ventilation. The third trimester is when the cerebral cortex, cerebellum, and retina develop. These areas are vulnerable to environmental influences if their development is interrupted. Throughout childhood and adolescence, neurodevelopmental defects have been linked to impaired cortical development and smaller brain volumes. Reduced cerebellar volumes have been linked to an increased risk of autism spectrum disorder, lower motor performance, impaired executive functioning, and poorer cognitive outcomes. The complete avascular retina, as well as the peripheral retina, should be treated during retinal ablation with laser photocoagulation (using a transpupillary diode, 11 argon, and three FD-YAG) or cryoablation as failing to do so promotes disease progression and results in unfavorable anatomical and refractive outcomes.

Discovery of Novel Myristic Acid Derivatives as N-Myristoyltransferase Inhibitors: Design, Synthesis, Analysis, Computational Studies and Antifungal Activity.

In recent years, N-Myristoyltransferase (NMT) has been identified as a new target for the treatment of fungal infections. It is observed that at present, there are increased rates of morbidity and mortality due to fungal infections. Hence, a series of novel myristic acid derivatives were designed via molecular docking studies and ADMET studies by targeting NMT (N-Myristoyltransferase). The designed myristic acid derivatives were synthesized by converting myristic acid into myristoyl chloride and coupling it with aryl amines to yield corresponding myristic acid derivatives. The compounds were purified and characterized via FTIR, NMR and HRMS spectral analyses. In this study, we carried out a target NMT inhibition assay. In the NMT screening assay results, the compounds 3u, 3m and 3t showed better inhibition compared to the other myristic acid derivatives. In an in vitro antifungal evaluation, the myristic acid derivatives were assessed against Candida albicans and Aspergillus niger strains by determining their minimal inhibitory concentrations (MIC50). The compounds 3u, 3k, 3r and 3t displayed superior antifungal capabilities against Candida albicans, and the compounds 3u, 3m and 3r displayed superior antifungal capabilities against Aspergillus niger compared to the standard drug FLZ (fluconazole). Altogether, we identified a new series of antifungal agents.

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 (Eugenia caryophyllata) 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. The synthesized compounds were structurally analyzed using FT-IR, 1HNMR, 13CNMR, and mass spectroscopy techniques. Molecular docking was performed to analyze binding free energy and important amino acids involved in the interaction between synthesized derivatives and the target protein. The development of the structure-activity relationship is based on computational studies. Additionally, the stability of the best-docked protein-ligand complexes was assessed using molecular dynamic modeling. The in-vitro PPARγ competitive binding Lanthascreen TR-FRET assay was used to confirm the affinity of compounds to the target protein. All the synthesized derivatives were evaluated for an in vitro anti-inflammatory activity using an albumin denaturation assay and HRBC membrane stabilization at varying concentrations from 6.25 to 400 µM. In this background, with the aid of computational research, we were able to design six novel derivatives of eugenol synthesized, analyzed, and utilized TR-FRET competitive binding assay to screen them for their ability to bind PPARγ. Anti-inflammatory activity evaluation through in vitro albumin denaturation and HRBC method revealed that 1f exhibits maximum inhibition of heat-induced albumin denaturation at 50% and 85% protection against HRBC lysis at 200 and 400 µM, respectively. Overall, we found novel derivatives of eugenol that could potentially reduce inflammation by PPARγ agonism.

Identification of the novel HLA-DPB1*1461:01 allele in three individuals from Southern India.

HLA-DPB1*1461:01 differs from DPB1*02:01:02:01 in exon 2, codon 51 CTG > CGG a Leucine to Arginine replacement.

Molecular dynamics articulated multilevel virtual screening protocol to discover novel dual PPAR α/γ agonists for anti-diabetic and metabolic applications.

PPARα and PPARγ are isoforms of the nuclear receptor superfamily which regulate glucose and lipid metabolism. Activation of PPARα and PPARγ receptors by exogenous ligands could transactivate the expression of PPARα and PPARγ-dependent genes, and thereby, metabolic pathways get triggered, which are helpful to ameliorate treatment for the type 2 diabetes mellitus, and related metabolic complications. Herein, by understanding the structural requirements for ligands to activate PPARα and PPARγ proteins, we developed a multilevel in silico-based virtual screening protocol to identify novel chemical scaffolds and further design and synthesize two distinct series of glitazone derivatives with advantages over the classical PPARα and PPARγ agonists. Moreover, the synthesized compounds were biologically evaluated for PPARα and PPARγ transactivation potency from nuclear extracts of 3T3-L1 cell. Furthermore, glucose uptake assay on L6 cells confirmed the potency of the synthesized compounds toward glucose regulation. Percentage lipid-lowering potency was also assessed through triglyceride estimate from 3T3-L1 cell extracts. Results suggested the ligand binding mode was in orthosteric fashion as similar to classical agonists. Thus molecular docking and molecular dynamics (MD) simulation experiments were executed to validate our hypothesis on mode of ligands binding and protein complex stability. Altogether, the present study developed a newer protocol for virtual screening and enables to design of novel glitazones for activation of PPARα and PPARγ-mediated pathways. Accordingly, present approach will offer benefit as a therapeutic strategy against type 2 diabetes mellitus and associated metabolic complications.

Approaches to engage an aging, rural cohort in southern India during the COVID-19 crisis and the psychological impact of COVID-19 in this cohort.

INTRODUCTION: The COVID-19 pandemic produced an unprecedented crisis across the world. Long-term cohort studies were stalled, including our longitudinal aging cohort study in rural India. METHODS: We describe approaches undertaken to engage with our cohort (n = 1830) through multiple rounds of calls and how we provided useful services to our subjects during the lockdown period. Consenting subjects also underwent telephonic assessments for depression and anxiety using validated, self-report questionnaires. RESULTS: Subjects reported benefitting from our telephonic engagement strategies, including the COVID-related safety awareness and counselling service. The proportion of subjects with depression increased from 7.42% pre-COVID to 28.97% post-COVID. DISCUSSION: We envisage that such engagement strategies would improve subject rapport and cohort retention, and thus, could be adopted by similar cohort studies across the world. This marginalized, rural Indian community had severe, adverse psychological impact in this pandemic. Urgent public health measures are needed to mitigate this impact and develop appropriate preventive strategies.

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. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.

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. The discovery of immune checkpoint inhibitors was started in the early 21st century; with some success through monoclonal antibodies, peptides, and small molecules. Being the most reliable and safest way to target immune checkpoints, the scientific community is exploring possibilities to develop small molecule inhibitors. Among the different scaffolds of the small molecule, the most exposed and researched core molecule is Biphenyl-based scaffolds. We have described all of the possible biphenyl-based small molecules in this article, as well as their interactions with various amino acids in the binding cavity. The link between the in silico, in vitro, and in vivo activities of the PD-1/PD-L1 inhibitors are well connected. The Tyr56, Met115, Ala121, and Asp122 were detected as the crucial amino acids of the PD-1/PD-L1 inhibition. Additionally, a detailed binding pocket analysis of the PD-L1 receptor was carried out, where it was observed and confirmed that the binding pocket is tunnel-shaped and hydrophobic in nature. Finally, the structure-activity relationship of the biphenyl-based small molecule inhibitors was developed based on their activity and the binding interactions.

Novel derivatives of eugenol as potent anti-inflammatory agents via 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. Compounds were screened for PPARγ protein binding by time-resolved fluorescence (TR-FRET) assay. The biochemical assay results were favorable for 1C which exhibited significant binding affinity with an IC50 value of 10.65 µM as compared to the standard pioglitazone with an IC50 value of 1.052 µM. In addition to the protein binding studies, as a functional assay, the synthesized eugenol derivatives were screened for in vitro anti-inflammatory activity at concentrations ranging from 6.25 µM to 400 µM. Among the four compounds tested 1C shows reasonably good anti-inflammatory activity with an IC50 value of 133.8 µM compared to a standard diclofenac sodium IC50 value of 54.32 µM. Structure-activity relationships are derived based on computational studies. Additionally, molecular dynamics simulations were performed to examine the stability of the protein-ligand complex, the dynamic behavior, and the binding affinity of newly synthesized molecules. Altogether, we identified novel eugenol derivatives as potential anti-inflammatory agents via PPARγ agonism.

Suppurative Pylephlebitis With Portal Vein Abscess Mimicking Portal Vein Thrombosis: A Report of Two Cases.

Suppurative pylephlebitis, that is, infected thrombosis of the portal vein and its branches is a rare condition with a high incidence of mortality and is often difficult to diagnose. We report two cases of suppurative pylephlebitis secondary to acute pancreatitis wherein the whole of the portal vein and its branches were transformed into an abscess cavity. The diagnosis was made after pus was seen coming out while the patient was taken up for portal vein thrombolysis. The pus was drained and the cavity was completely evacuated leading to recovery from this infection. These two cases highlight the fact that suppurative pylephlebitis is rare and extremely difficult to diagnose as it mimics portal vein thrombosis, but a high degree of suspicion in critically ill patients with thrombus-like appearance in portal vein having a uniform and homogeneous portal venous content on magnetic resonance imaging not responding to antibiotic therapy may be considered for aspiration for differentiating from thrombus and management.

Evaluation of flavonoids from banana pseudostem and flower (quercetin and catechin) as potent inhibitors of α-glucosidase: An in silico perspective.

The amelioration of postprandial hyperglycemia in diabetic conditions could be accomplished by the inhibition of α-glucosidases, a set of intestinal carbohydrate digestive enzymes responsible for starch hydrolysis and its absorption. The ethnopharmacological profile of banana depicts the usage of different plant parts in conventional medicinal formulations. The antidiabetic studies of the plant have demonstrated their ability to inhibit α-glucosidase. Besides, our research group has reported the α-glucosidase inhibitory potential of the banana pseudostem and flower extracts in previous studies. In this study, we deliberate on the specific phytoconstituents of banana pseudostem and flower to evaluate their antidiabetic effects through an in silico perspective for the α-glucosidase inhibition. In this context, several phytoconstituents of banana pseudostem and flower identified through GC-MS analysis were retrieved from chemical databases. These phytochemicals were virtually screened through the molecular docking simulation process, from which only two flavonoids (catechin and quercetin) were selected based on their binding affinity and extent of interaction with the α-glucosidase target protein. The lower binding affinities of catechin and quercetin in comparison with that of acarbose as a control proved their binding efficiency with the target protein. In addition, acarbose showed subservient molecular interaction, forming an unfavourable acceptor-acceptor bond. The molecular dynamics simulations also depicted the effective binding and stability of the complexes formed with catechin and quercetin, in comparison with that of acarbose. Further, PASS analysis, druglikeliness, and pharmacokinetic assessments showed that both catechin and quercetin edge over acarbose in terms of drug-score and pharmacokinetic properties. With the positive results obtained from contemporary strategies, the two flavonoids from banana pseudostem and flower might be established as a considerable phototherapeutic approach to inhibit α-glucosidase. Communicated by Ramaswamy H. Sarma.

Multi-conformational frame from molecular dynamics as a structure-based pharmacophore model for mapping, screening and identifying ligands against PPAR-γ: a new protocol to develop promising candidates.

Despite intensive research on clinical and molecular factors, the development of antidiabetic drugs in the last few decades is decelerating and as a result, the number of drugs approved by the US FDA is reduced. Hence, there is a persistent need for the innovative development of novel anti-diabetic drugs. Recent studies have provided ample proof that the peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor and its co-activator PGC-1 alpha may serve as good candidates for the treatment of several metabolic disorders. Therefore, in this study, 50 ns molecular dynamics (MD) simulations of the ligand-receptor complex were carried out and the most populated cluster of rosiglitazone bound to crucial amino acids during dynamics studies were selected to generate multi-conformation frame and further dynamic pharmacophore models. Finally, three pharmacophore models were generated, and 10 hits were retrieved as final lead candidates by virtual screening of ZINC database and molecular docking. The study reveals that the amino acids Met364, Lys367, His449, Leu453, Leu469, and Tyr473 play a crucial role in the binding of the compounds at the active site of PPARγ and the selected compounds from the ZINC database showed promising binding as compared to rosiglitazone. Further, ADMET studies were carried out to define the pharmacokinetic properties of promising PPARγ ligand candidates.Communicated by Ramaswamy H. Sarma.

Peroxisome Proliferator-activated Receptor-γ As A Novel and Promising Target For Treating Cancer Via Regulation of Inflammation: A Brief Review.

Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors and the ligand-activated intracellular transcription factors that are known to play a key role in physiological processes such as cell metabolism, proliferation, differentiation, tissue remodeling, inflammation, and atherosclerosis. However, in the past two decades, many reports claim that PPARs also play an imperious role as a tumor suppressor. PPAR- gamma (PPARγ), one of the best-known from the family of PPARs, is known to express in colon, breast, bladder, lung, and prostate cancer cells. Its function in tumour cells includes the modulation of several pathways involved in multiplication and apoptosis. The ligands of PPARγ act by PPARγ dependent as well as independent pathways and are also found to regulate different inflammatory mediators and transcription factors in systemic inflammation and in tumor microenvironment. Both synthetic and natural ligands that are known to activate PPARγ, suppress the tumor cell growth and multiplication through the regulation of inflammatory pathways, as found out from different functional assays and animal studies. Cancer and inflammation are interconnected processes that are now being targeted to achieve tumor suppression by decreasing the risks and burden posed by cancer cells. Therefore, PPARγ can serve as a promising target for development of clinical drug molecule attenuating the proliferation of cancer cells. In this perspective, this mini review highlights the PPARγ as a potential target for drug development aiming for anti-inflammatory and thereby suppressing tumors.

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. The compounds exhibited activity ranging from weak to significant in terms of percentage cytotoxicity which is proportional to the anticancer activity. Amongst the screened compounds, compounds 4, 6 and 8 exhibited potential anticancer activity. Furthermore, CoMSIA studies were performed to derive the structure activity relationships in a 3D grid space by plotting experimental vs predicted cytotoxic activities. We have an opinion that, this developed model helps us in future to develop more potential 1,4-dihydropyrimidines for their cytotoxicity or anticancer activity.

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. Among the 10 hypotheses generated, Hypotheses 2 showed the highest correlation coefficient values of 0.95 with less RMS deviation of 1.193. Validation of the developed pharmacophore model was performed by Fischer's randomization and screening against test and decoy set. The GH score or goodness score was found to be 0.81 indicating moderate to a good model. The selected pharmacophore model Hypo 2 was used as a query model for further screening of 11,145 compounds from the PubChem, sc-PDB structure database, and designed novel ligands. Based on fit values and ADMET filter, the final 10 compounds with the predicated activity of ≤ 3 nM were subjected for docking analysis. Docking analysis revealed the unique binding mode with hydrophobic amino acid that can cause destabilization of the H12 which is an important molecular mechanism to prove its antagonist action. Based on high CDocker scores, Cpd31 was synthesized, purified, analyzed and screened for PPARγ competitive binding by TR-FRET assay. The biochemical protein binding results matched the predicted results. Further, Cpd31 was screened against cancer cells and validated the results.

Glitazones Activate PGC-1α Signaling via PPAR-γ: A Promising Strategy for Antiparkinsonism Therapeutics.

Understanding various aspects of Parkinson's disease (PD) by researchers could lead to a better understanding of the disease and provide treatment alternatives that could significantly improve the quality of life of patients suffering from neurodegenerative disorders. Significant progress has been made in recent years toward this goal, but there is yet no available treatment with confirmed neuroprotective effects. Recent studies have shown the potential of PPARγ agonists, which are the ligand activated transcriptional factor of the nuclear hormone superfamily, as therapeutic targets for various neurodegenerative disorders. The activation of central PGC-1α mediates the potential role against neurogenerative diseases like PD, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. Further understanding the mechanism of neurodegeneration and the role of glitazones in the activation of PGC-1α signaling could lead to a novel therapeutic interventions against PD. Keeping this aspect in focus, the present review highlights the pathogenic mechanism of PD and the role of glitazones in the activation of PGC-1α via PPARγ for the treatment of neurodegenerative disorders.