Design, synthesis, biological assessment and molecular modeling studies of novel imidazothiazole-thiazolidinone hybrids as potential anticancer and anti-inflammatory agents.

A new series of imidazothiazole derivatives bearing thiazolidinone moiety (4a-g and 5a-d) were designed, synthesized and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer and anti-inflammatory activity, cardiomyopathy toxicity and hepatotoxicity. Compound 4c inhibited EGFR kinase at a concentration of 18.35 ± 1.25 µM, whereas standard drug erlotinib showed IC50 value of 06.12 ± 0.92 µM. The molecular docking, dynamics simulation and MM-GBSA binding energy calculations revealed strong interaction of compound 4c with binding site of EGFR. The synthesized compounds were evaluated for their anticancer activity by MTT assay against three human cancer cell lines A549 (Lung), MCF-7 (Breast), HCT116 (Colon), one normal human embryonic kidney cell line HEK293 and also for their EGFR kinase inhibitory activity. Few compounds of the series (4a, 4b, 4c) showed promising growth inhibition against all the tested cancer cell lines and against EGFR kinase. Among these, compound 4c was found to be most active and displayed IC50 value of 10.74 ± 0.40, 18.73 ± 0.88 against cancer cell lines A549 and MCF7 respectively whereas it showed an IC50 value of 96.38 ± 1.79 against HEK293 cell line indicating lesser cytotoxicity for healthy cell. Compounds 4a, 4b and 4c were also examined for their apoptosis inducing potential through AO/EB dual staining assay and it was observed that their antiproliferative activity against A549 cells is mediated via induction of apoptosis. Cardiomyopathy studies showed normal cardiomyocytes with no marked sign of pyknotic nucleus of compounds 4b and 4c. Hepatotoxicity studies of compounds 4b and 4c also showed normal architecture of hepatocytes. Compounds 4a-g and 5a-d were also evaluated for their in-vitro anti-inflammatory activity by protein albumin denaturation assay. Among the tested compounds 4a-d and 5a-b showed promising activity and were selected for in-vivo inflammatory activity against carrageenan rat paw edema test. Among these compounds, 4b was found to be most active in the series showing 84.94% inhibition, whereas the standard drug diclofenac sodium showed 84.57% inhibition. Compound 4b also showed low ulcerogenic potential and lipid peroxidation. Thus, compounds 4c and 4b could be a promising lead compounds for developing anticancer and anti-inflammatory agents with low toxicity and selectivity.

Discovery of novel PARP-1 inhibitors using tandem in silico studies: integrated docking, e-pharmacophore, deep learning based de novo and molecular dynamics simulation approach.

Cancer accounts for the majority of deaths worldwide, and the increasing incidence of breast cancer is a matter of grave concern. Poly (ADP-ribose) polymerase-1 (PARP-1) has emerged as an attractive target for the treatment of breast cancer as it has an important role in DNA repair. The focus of the study was to identify novel PARP-1 inhibitors using a blend of tandem structure-based screening (Docking and e-pharmacophore-based screening) and artificial intelligence (deep learning)-based de novo approaches. The scrutiny of compounds having good binding characteristics for PARP-1 was carried out using a tandem mode of screening along with parameters such as binding energy and ADME analysis. The efforts afforded compound Vab1 (PubChem ID 129142036), which was chosen as a seed for obtaining novel compounds through a trained artificial intelligence (AI)-based model. Resultant compounds were assessed for PARP-1 inhibition; binding affinity prediction and interaction pattern analysis were carried out using the extra precision (XP) mode of docking. Two best hits, Vab1-b and Vab1-g, exhibiting good dock scores and suitable interactions, were subjected to 100 nanoseconds (ns) of molecular dynamics simulation in the active site of PARP-1 and compared with the reference Protein-Ligand Complex. The stable nature of PARP-1 upon binding to these compounds was revealed through MD simulation.Communicated by Ramaswamy H. Sarma.

Exosomes: current knowledge and future perspectives.

Exosomes are membrane-bound micro-vesicles that possess endless therapeutic potential for treatment of numerous pathologies including autoimmune, cardiovascular, ocular, and nervous disorders. Despite considerable knowledge about exosome biogenesis and secretion, still, there is a lack of information regarding exosome uptake by cell types and internal signaling pathways through which these exosomes process cellular response. Exosomes are key components of cell signaling and intercellular communication. In central nervous system (CNS), exosomes can penetrate BBB and maintain homeostasis by myelin sheath regulation and the waste products elimination. Therefore, the current review summarizes role of exosomes and their use as biomarkers in cardiovascular, nervous and ocular disorders. This aspect of exosomes provides positive hope to monitor disease development and enable early diagnosis and treatment optimization. In this review, we have summarized recent findings on physiological and therapeutic effects of exosomes and also attempt to provide insights about stress-preconditioned exosomes and stem cell-derived exosomes.

Identification of behenic acid as medicinal food for the diabetes mellitus: structure-based computational approach and molecular dynamics simulation studies.

Vegetables, fruits, and spices have a pivotal role in maintaining the metabolism and have diversified health welfares. The food products have medicinal values (Medifood) and benefitted prophylactically and simultaneously; health experts recommend them due to their synergistic effect on medicine. Therefore, research thrusts have developed medifood and counted in the field of pharma-nutrition. Type II diabetes mellitus is one of the foremost progressive metabolic disorders, which affects several millions of people around the globe due to ignorance of food habits. Improvement in lifestyle and intake of habitual food may improve the diabetic conditions. In the present study, we performed in silico studies of fatty acids on the free fatty acid 1 receptor to identify fatty acids readily available in daily food content. Additionally, molecular dynamic simulation study to recognize the dynamic behavior of protein-fatty acid complex. The in silico results suggest that 04 fatty acids may be promising in which behenic acid was most potential and showed binding energy of - 110.857 kcal/mol. The stability of the protein-ligand complex is confirm in simulation studies, with occupancy of 95% and 84%, respectively. Behenic acid is present in different parts of the Moringa tree and may serve as medifood in type II diabetes mellitus.

Identification of Mpro inhibitors of SARS-CoV-2 using structure based computational drug repurposing.

The recent outbreak of COVID-19, caused by the novel pathogen SARS-coronavirus 2 (SARS-CoV-2) is a severe health emergency. In this pandemic, drug repurposing seems to be the most promising alternative to identify effective therapeutic agents for immediate treatment of infected patients. The present study aimed to evaluate all the drugs present in drug bank as potential novel SARS-CoV-2 inhibitors, using computational drug repurposing studies. Docking-based virtual screening and binding energy prediction were performed, followed by Absorption Distribution Metabolism Excretion calculation. Hydroxychloroquine and Nelfinavir have been identified as the best potential inhibitor against the SARS-CoV-2, therefore, they were used as reference compounds in computational DR studies. The docking study revealed 13 best compounds based on their highest binding affinity, binding energy, and dock score concerning the other screened compounds. Out of 13, only 4 compounds were further shortlisted based on their binding energy and best ADME properties. The hierarchical virtual screening yielded the best 04 drugs, DB07042 (compound 2), DB13035 (compound 3), DB13604 (compound 5) and DB08253 (compound 6), with commendable binding energies in kcal/mol, i.e. -65.45, -62.01, -52.09 and -51.70 respectively. Further, Molecular dynamics simulation with 04 best-retrieved hits has confirmed stable trajectories in protein in terms of root mean square deviation and root mean square fluctuation. During 30 ns simulation, the interactions were also found similar to the docking-based studies. However, clinical studies are necessary to investigate their therapeutic use against this outbreak.

Structure based docking and molecular dynamics studies: Peroxisome proliferator-activated receptors -α/γ dual agonists for treatment of metabolic disorders.

Diabetes is a foremost health problem globally susceptible to increased mortality and morbidity. The present therapies in the antidiabetic class have sound adverse effects and thus, emphasis on the further need to develop effective medication therapy. Peroxisome proliferator-activated receptor alpha-gamma dual approach represents an interesting target for developing novel anti-diabetic drug along with potential anti-hyperlipidimic activity. In the current study, the peroxisome proliferator-activated receptor alpha-gamma agonistic hits were screened by hierarchical virtual screening of drug like compounds followed by molecular dynamics simulation and knowledge-based structure-activity relation analysis. The key amino acid residues of binding pockets of both target proteins were acknowledged as essential and were found to be associated in the key interactions with the most potential dual hit. This dual targeted approach of structure based computational technique was undertaken to identify prevalent promising hits for both targets with binding energy and absorption distribution metabolism excretion prediction supported the analysis of their pharmacokinetic potential. In addition, stability analysis using molecular dynamics simulation of the target protein complexes was performed with the most promising dual targeted hit found in this study. Further, comparative analysis of binding site of both targets was done for the development of knowledge-based structure-activity relationship, which may useful for successful designing of dual agonistic candidates. AbbreviationsADMEabsorption distribution metabolism excretionHTVShighthroughput virtual screeningMDmolecular dynamicsMMGBSAmolecular mechanics generalized bonn solvation accessiblePDBprotein data bankPPARperoxisome proliferator-activated receptorRMSDRoot mean square deviationRMSFRoot mean square fluctuationSARstructural activity relationshipSPsimple precisionT2DMTypeII diabetes mellitusXPExtra precisionCommunicated by Ramaswamy H. Sarma.

Identification of novel G-protein-coupled receptor 40 (GPR40) agonists by hybrid in silico-screening techniques and molecular dynamics simulations thereof.

Diabetes is a major health problem worldwide predisposing to increased mortality and morbidity. The current antidiabetic therapies have serious side effects and thus have emphasis on further need to develop effective medication therapy. Free fatty acid1 receptor (FFA1R) or G-protein-coupled receptor 40 (GPR40) represents an interesting target for developing novel antidiabetic drug. In the current study, the FFA1R agonistic activity of drug-like molecules was screened by employing pharmacophore modeling, docking, and molecular dynamics (MD) simulation. Hierarchical screening of virtual library of drug-like compounds was performed. This combined computational approach of pharmacophore mapping and structure-based approach was used to identify common hits, and the absorption, distribution, metabolism and excretion (ADME) prediction supported the analysis of their pharmacokinetic potential. MD simulation studies of the GPR40 complex with the most promising hit found in this study further validated are approached. The key residues Arg183, Arg258, Tyr91, and Tyr240 of the binding pocket were acknowledged as essential and were found to be associated in the key interactions with the most potential hit. These studies will hopefully provide scope for efficiently designing and screening new compounds as active drug candidates with more selectivity for hGPR40. To the best of our knowledge, this is the first example of the successful application of both ligand and structurebased virtual-screening techniques to discover novel GPR40 agonists. Communicated by Ramaswamy H. Sarma.

Norbixin, an apocarotenoid derivative activates PPARγ in cardiometabolic syndrome: Validation by in silico and in vivo experimental assessment.

The increased prevalence of cardio-metabolic disorders worldwide prompted the exploration of new strategies for its treatment. Peroxisome Proliferator activated receptor (PPAR) play major role in regulation of lipid as well as glucose metabolism and thus, natural PPARγ activators seem to be drug of choice. AIMS: In the present work, we studied norbixin which is a natural apocarotenoid derivative for its agonistic activity for PPAR γ followed by in vivo studies for amelioration of cardio-metabolic syndrome (CMetS). MAIN METHODS: The methods include computational studies, TR-FRET binding analysis and in vivo studies on high fat diet induced rats. KEY FINDINGS: Molecular docking and molecular dynamics (MD) simulation studies showed that norbixin could be embedded into hydrophobic pocket of PPARγ and stable hydrogen bonding interactions were found with residues Glu273, Tyr327, Ser289, His323, His449 and Tyr473 of PPARγ. These results were substantiated by significant in vitro PPAR agonistic activity of norbixin in TR-FRET binding assay studies. The experimental results of norbixin in high fat diet induced CMetS in rats further confirmed that norbixin decreased insulin resistance (IR), hyperglycemia and dyslipidemia. These results were accompanied by reduced inflammatory marker hs-CRP as well as decreased oxidative stress and arterial pressure. The histopathology of heart sections also showed that norbixin could prevent the abnormal fibrotic changes in heart. Furthermore, PPARγ protein expressions were increased, whereas NF-κB expression was decreased by norbixin treatment in western blot studies. SIGNIFICANCE: These results validate norbixin as a novel PPARγ agonist and prove therapeutic potential of norbixin in treatment of CMetS.

Peristome as a potential tool for delimiting Bryum Hedw. (Bryaceae) from India.

The peristome, an interesting and important taxonomic structure used in the systematics of mosses, is for the first time studied in detail for 21 taxa of Bryum, which constitute a fraction of Indian representatives. Macro- and micro-morphological characters including color, size and length of two components of peristome, tapering pattern, median line, and papillosity at upper part under light microscope; width of exostome border, number and inner surface of ventral trabeculae, presence or absence of longitudinal/oblique septae between ventral trabeculae, pattern of exostome surface and height of endostomial basal membrane, adherence, perforations, and surface of cilia under scanning electron microscope were examined to bring out submicroscopic differences. Detail surface structure of eight taxa, viz., B. apalodictyoides, B. evanidinerve, B. pachytheca, B. pseudotriquetrum var. subrotundum, B. reflexifolium, B. thomsonii, B. tuberosum, and B. turbinatum, under LM and nine species, namely, B. apalodictyoides, B. apiculatum, B. argenteum, B. billarderi, B. dichotomum, B. evanidinerve, B. recurvulum, B. turbinatum, and B. uliginosum, under SEM is being provided for the first time. Description of peristome surface and a key based on SEM and other taxonomical features is also being provided. The data obtained from the present study suggest that the species of this genus can easily be distinguished on the basis of peristomial surface pattern.

Deciphering PPARγ activation in cardiometabolic syndrome: studies by in silico and in vivo experimental assessment.

Cardiometabolic syndrome (CMetS) is a consolidation of metabolic disorders characterized by insulin resistance, dyslipidemia and hypertension. Curcumin, a natural bioactive compound, has been shown to possess notable anti-oxidant activity and it has also been included as a super natural herb in the super natural herbs database. Most of the beneficial effects of Curcumin are possibly due to activation of the nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigates molecular interactions of curcumin with PPARγ protein through molecular docking and molecular dynamics (MD) simulation studies. Further, effect of curcumin on high fat diet induced CMetS was studied in rats along with western blot for PPARγ and nuclear factor-κB (NF-κB) expressions and histopathological studies. Computational studies presented several significant molecular interactions of curcumin including Ser289, His323, His449 and Tyr473 of PPARγ. The in vivo results further confirmed that curcumin was able to ameliorate the abnormal changes and also, increased PPARγ expressions. The results confirm our hypothesis that activation of PPARγ by curcumin possesses the therapeutic potential to ameliorate the altered levels of metabolic changes in rats in the treatment of CMetS. This is the first report of CMetS treatment by curcumin and study of its underlying mechanism through in silico as well as in vivo experiments.

Antibacterial activity of some bryophytes used traditionally for the treatment of burn infections.

CONTEXT: Plagiochasma appendiculatum L. & L. (Aytoniaceae), Conocephalum conicum (L.) Necker (Conocephalaceae), Bryum argenteum Hedw. (Bryaceae), and Mnium marginatum (With.) P. Beauv. (Mniaceae) are bryophytes (liverworts and mosses) used by traditional healers for the treatment of burn, cuts, wounds, and skin disorders. OBJECTIVE: This study evaluated the antibacterial activity of four bryophytes against some common bacteria responsible for burn infections. MATERIALS AND METHODS: Different fractions of bryophytes were screened using the disc diffusion (qualitative) and broth microdilution (quantitative) methods, according to the guidelines of the National Committee for Clinical and Laboratory Standards. RESULTS AND DISCUSSION: Chloroform fractions of liverworts were more active against Gram negative strains while butanol fractions of mosses had significant activity against Gram positive bacteria. Staphylococcus aureus was the most sensitive strain of those tested with the butanol fraction of M. marginatum (moss), with the strongest inhibition zone of 102.92% and minimum inhibitory concentration of 30 µg mL(-1). CONCLUSION: Our findings support the use of the bryophytes in traditional medicine for burn infections because of their significant antibacterial activity.

Antimicrobial, wound healing and antioxidant activity of Plagiochasma appendiculatum Lehm. et Lind.

Plagiochasma appendiculatum (Aytoniaceae) of the order Marchantiales is widely used in the form of paste ethnomedicinally by Gaddi tribe in Kangra valley for treating skin diseases. In this context, antimicrobical potential of Plagiochasma appendiculatum against a wide range of microorganisms was studied. To validate the ethnotherapeutic claims of the plant in skin diseases, wound healing activity was studied, besides antioxidant activity to understand the mechanism of wound healing activity. The plant (alchoholic and aqueous extract) showed significant antibacterial and antifungal activity against almost all the organisms: Micrococcus luteus, Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Streptococcus pneumoniae, Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella typhimurium, and eight fungi Candida albicans and Cryptococcus albidus-dimorphic fungi, Trichophyton rubrum-dermatophyte fungi, Aspergillus niger, Aspergillus flavus, Aspergillus spinulosus, Aspergillus terreus and Aspergillus nidulans-systemic fungi, with especially good activity against the dermatophyte (Trichophyton rubrum) and some infectious bacteria (Escherichia coli, Proteus mirabilis and Salmonella typhimurium) with an MIC of 2.5 microg/disc. The results show that Plagiochasma appendiculatum extract has potent wound healing capacity as evident from the wound contraction and increased tensile strength. The results also indicated that Plagiochasma appendiculatum extract possesses potent antioxidant activity by inhibiting lipid peroxidation and increase in the superoxide dismutase (SOD) and Catalase activity.