In Silico Designing of Novel Thiazolidine-2-one Derivatives as Dual PDE4/7 Inhibitors for Inflammatory Disorders

Phosphodiesterase 4 (PDE4) and phosphodiesterase 7 (PDE7), members of PDE super family, catalyse metabolism of secondary messenger cyclic adenosine monophosphate leading to augmented inflammatory processes in pro-inflammatory and immune-modulatory cells. Dual inhibitors of PDE4/7 are a novel class of drug candidates which can regulate pro-inflammatory as well as function of immune T-cell and are particularly beneficial for the treatment of various inflammatory diseasesdevoid of unwanted actions. Intense efforts have been directed towards the development of effective dual inhibitors of both PDE4 and PDE7, but not much success has been reported till yet. The aim of present study was to design some newer substituted thiazolidine-2-one derivatives as dual inhibitors of PDE4/7 using structure based rational drug design approach. A new series of thiazolidine-2-one analogues were designed and molecular docking was performed using AutoDock Vina to explore the bondinginteractions of the designed molecules with the amino acid residues in the active site of target proteins. The docking study indicated that all the substituted thiazolidine-2-one derivatives have appreciable binding interactions with protein residues of both PDE4 and PDE7. The newly designed compounds could be used as lead molecules for development potent and non-toxic dual inhibitors of PDE4/7 for the management of various inflammatory conditions

Molecular Docking Studies of Phenolic Compounds from Syzygium cumini with Multiple Targets of Type 2 Diabetes

Treatment of type 2 diabetes without any side effects is still a challenge to the medical system. This leads to increasing demand for natural products with antidiabetic activity with fewer side effects. Syzygium cumini is a traditional herbal medicinal plant and is reported to possess a variety of pharmacological actions. It contains various types of chemical constituents including terpenoids, tannins, anthocyanins, flavonoids and other phenolic compounds. Some flavonoids and other phenolic compounds from S. cumini were reported in literature to have type 2 antidiabetic potential. The main objective of the current investigation was in silico screening of some phenolic compounds from S. cumini against multiple targets associated with type 2 diabetes to explore the mechanism of antidiabetic action and prediction of binding mode using molecular docking studies. In silico docking studies were performed for the selected molecules in the binding site of multiple targets associated with type 2 diabetes (α-glucosidas , dipeptidyl peptidase 4, glycogen synthase kinase 3, glucokinase and glucagon receptor). Amongst the compounds tested in silico, rutin showed appreciable binding with multiple targets of type 2 diabetes including α-glucosidase, dipeptidyl peptidase 4, glycogen synthase kinase 3, and glucagon receptor. Catechin was found to inhibit both α-glucosidase, and dipeptidyl peptidase 4. This information can be utilized for the design and development of potent multi-functional candidate drugs with minimal side effects for type 2 diabetes therapeuticsa

Molecular Docking Evaluation of Some Natural Phenolic Compounds as Aldose Reductase Inhibitors for Diabetic Complications

The enzyme aldose reductase (AR) is a member of aldoketoreductase super-family which catalyzes the formation of sorbitol from glucose through polyol pathway of glucose catabolism. Reduced sorbitol production via polyol pathway due to AR inhibition is a target of choice for controlling major complications of diabetes. Epalrestat is the only commercially available inhibitor of AR till date,thus, there is a great need to search for more economical, nontoxic and safer inhibitors of AR enzyme. Flavonoids,the polyphenol compounds in plants have been reported for inhibitory effects against AR. The objective of this study is to explore the binding modes of naturalphenolic compounds with AR to design safer natural drugs as alternatives to synthetic drugs. We conducted a molecular docking study on some naturalphenolic compounds with AR enzyme in complex with the synthetic inhibitor. The overlay of the docked pose of the selected natural phenols with the ARreference inhibitor complex showed that the selected natural compounds have the similar binding pattern with the active site residues of the enzyme as that of co-crystallized inhibitor. The results of docking study showed the best binding affinity of AR with that of 2-(4-hydroxy-3-methoxyphenyl) ethanoic acid and butein, having the lowest binding free energy of –9.8 kcal/mol and–9.7 kcal/mol, respectively. This information can be utilized to design potent, economical and non-toxic natural AR inhibitors from natural phenols for the therapeutics of diabetic complications

SURFACE MODIFICATION OF RING-TRAVELER OF TEXTILE SPINNING MACHINE FOR SUBSTANTIALITY

In this report, a study of the wear mechanisms involved in spinning Ring and Traveler of textile industry have been presented. These components, after surface processing with various coatings techniques, were analyzed on the test rig to analyze the wear mechanism. The objective was accomplished by comparing various plasma sprayed coatings on E52100 steel pins using a Pin-on-Disc machine. The surface morphology as well as mechanical properties of the deposited coatings namely WC-Co-Cr, Al2O3+TiO2 (Alumina-Titania) and Cr3C2NiCr, as well as uncoated E52100, were comparatively studied. This study elucidates towards improving the working life of the Ring in a Textile mill while spinning operation. An X-ray diffractometer (XRD) and Scanning Electron Microscope (SEM) was employed to characterize the unworn and worn surfaces of the specimens. The study revealed that the wear rate of Plasma sprayed thermal coatings enhanced with augmenting load. The Plasma sprayed WC-Co-Cr, Cr3C2NiCr, Al2O3+13TiO2 coatings developed on workpiece pins exhibited a notable decrease in volume loss of the material as compared to uncoated E52100 substrate. WC-Co-Cr coating turned out to be the best performer in terms of lowest cumulative volume loss among all the variants of coatings

Role of Protein Kinase C in Diabetic Complications

Diabetes is the most common and systemic disorder associated with hyperglycemia which is the significant factor in the development of micro- and macrovascular changes. Many mechanistic approaches i.e. activation of Protein kinase C, glycation end products production, hexosamine pathway and polyol pathway induce cellular damage and lead to the development of diabetic complications like nephropathy, neuropathy, retinopathy, and myopathy. One of the adverse effects of long-lasting hyperglycemia is activation of PKC (intracellular signaling enzyme) and has become a field of great research interest. Hence, in this review special emphasis is placed on microvascular complications which are due to activation of PKC. Clinical trials have also been conducted using selective PKC inhibitors and have shown positive results against hyperglycemia

Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases

Effect of clonidine and/or fentanyl in combination with intrathecal bupivacaine for lower limb surgery

Background: Various adjuncts to local anesthetics have been used with the purpose of improving the quality of subarachnoid block. This randomized double-blind study was conducted to evaluate the efficacy of adding clonidine to bupivacaine and bupivacaine-fentanyl combination. Materials and Methods: A total of 100 patients scheduled for surgery under spinal anesthesia were randomly allocated into four groups (n = 25 each) to receive intrathecal bupivacaine 7.5 mg plus normal saline 0.5 ml (group BS), intrathecal bupivacaine 7.5 mg, and fentanyl 25 μg (group BF), intrathecal bupivacaine 7.5 mg and clonidine 75 μg (group BC), intrathecal bupivacaine 7.5 mg, clonidine 37.5 μg, and fentanyl 12.5 μg (group BCF). Results: The time of onset of sensory block (min) in groups BS, BC, BCF, and BF was 10.80 ± 2.26, 10.20 ± 1.00, 10.00 ± 0.00, and 13.80 ± 2.61 respectively, thus onset of sensory block was significantly earlier in groups BC and BCF. Similarly, onset of motor block was also quicker in groups BC and BCF. Time of requirement of supplemental analgesia was 135.20 ± 12.70 min, 199.2 ± 21.92 min, 209.80 ± 26.32 min, and 208.00 ± 26.58 min in groups BS, BF, BC, and BCF respectively. Intraoperative and postoperative changes in heart rate, mean arterial blood pressure, oxygen saturation, and respiratory rate were comparable. Sedation scores were significantly higher in group BC. Pruritus was only observed in groups BF and BCF. Mean nausea vomiting scores were comparable in all groups. Conclusion: We conclude that the addition of clonidine in doses of 75 μg and 37.5 μg to low-dose bupivacaine and bupivacaine-fentanyl prolongs the sensory and motor block while increasing the duration of postoperative analgesia without significant side-effects