Ameliorative effect of rubiadin-loaded nanocarriers in STZ-NA-induced diabetic nephropathy in rats: formulation optimization, molecular docking, and in vivo biological evaluation.

Diabetic nephropathy (DN) is a significant source of end-stage renal illness all over the world in both developed and developing countries. The aim of the study was to optimize rubiadin-loaded niosomes (RLN) using Box-Behnken design for the management of streptozotocin-nicotinamide (STZ-NA)-induced DN in Wistar rats. The RLN were formulated by a "thin-layer hydration technique." The optimization of RLN was done by Box-Behnken design; the independent variables were cholesterol (CHOL), Span 80, and methanol, while the dependent factors were the vesicle size, zeta potential, and entrapment efficiency. The optimized formulation was characterized for various biochemical parameters including anti-diabetic activity in Wistar rats. The optimized RLN presented vesicle size of 238 nm, zeta potential -68 mV, and entrapment efficiency 85%. A noteworthy decreased in blood glucose level was detected in STZ-NA-induced DN rats when orally treated with RLN (100 mg/kg/week and 200 mg/kg/week). Oral administration of RLN formulation considerably decreased the levels of urea, uric acid, and creatinine in DN rats. In addition, treatment of DN rats with RLN formulation considerably improves the level of TBARS, GSH, SOD, and CAT. The lipid profile of DN rats was also improved on treatment with RLN formulation. This study revealed that the prepared RLN formulation was successfully optimized by Box-Behnken design and found to be useful for the management of STZ-NA-induced DN in Wistar rats.

Alogliptin reversed hippocampal insulin resistance in an amyloid-beta fibrils induced animal model of Alzheimer's disease.

The complications of Alzheimer's disease (AD) have made the development of its treatment a challenging task. Several studies have indicated the disruption of insulin receptor substrate-1 (IRS-1) signaling during the development and progression of AD. The role of a dipeptidyl peptidase-4 (DPP-4) inhibitor on hippocampal IRS-1 signaling has not been investigated before. In this study, we evaluated the efficacy of alogliptin (DPP-4 inhibitor) on hippocampal insulin resistance and associated AD complications. In the present study, amyloid-ß (1-42) fibrils were produced and administered intrahippocampally for inducing AD in Wistar rats. After 7 days of surgery, rats were treated with 10 and 20 mg/kg of alogliptin for 28 days. Morris water maze (MWM) test was performed in the last week of our experimental study. Post 24 h of final treatment, rats were euthanized and hippocampi were separated for biochemical and histopathological investigations. In-silico analysis revealed that alogliptin has a good binding affinity with Aß and beta-secretase-1 (BACE-1). Alogliptin significantly restored cognitive functions in Aß (1-42) fibrils injected rats during the MWM test. Alogliptin also significantly attenuated insulin level, IRS-1pS307 expression, Aß (1-42) level, GSK-3ß activity, TNF-α level and oxidative stress in the hippocampus. The histopathological analysis supported alogliptin mediated neuroprotective and anti-amyloidogenic effect. Immunohistochemical analysis also revealed a reduction in IRS-1pS307 expression after alogliptin treatment. The in-silico, behavioral, biochemical and histopathological analysis supports the protective effect of alogliptin against hippocampal insulin resistance and AD.

Identification of novel small molecule non-peptidomimetic inhibitor for prolyl oligopeptidase through in silico and in vitro approaches.

Prolyl oligopeptidase (POP) enzyme has been studied for various disorders, viz. Schizophrenia, Alzheimer's, Parkinson's, Depression, Inflammation, etc., for three decades, but no drug has passed through the clinical trials, possibly because of indigent pharmacokinetics. This might have been a result of similar structures of drug candidates. This study aimed at identifying novel small non-peptidomimetic inhibitors for POP enzyme that could serve as a lead for developing newer drugs. Structure-based virtual screening of molecules of MolMall database was conducted on the POP enzyme (PDB ID 3DDU) to identify potential hits. The hits identified were subjected to computational pharmacokinetic screening followed by molecular mechanics/generalized Born and surface area studies to estimate the binding free energy of the docked complexes. After that, nine hits were selected and tested for POP inhibitory activity, among which one compound MM 4 was found to be most potent with EC50 of 100 µM. Compound MM 4 was further subjected to molecular dynamics simulations to study the overall stability of the ligand-protein complex. The compound interacted strongly with catalytic amino acid Arg643 by forming salt and water bridges; it also interacted well with amino acids Phe173, Arg252 and Met235. This study provides a lead molecule for further development of POP inhibitors.Communicated by Ramaswamy H. Sarma.

Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated in silico approaches.

The dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure-based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these in silico techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure-based screening against PDB ID: 5T4E. After absorption, distribution, metabolism and excretion (ADME) analysis of shortlisted compounds, consensus docking and molecular mechanics/generalized born surface area studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall-20062) was available which was procured through exchange program. Molecular dynamic simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound MolMall-20062 showed promising DPP-IV inhibition activity with IC50: 6.2 µM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors.AbbreviationsADMEabsorption, distribution, metabolism and excretionChEBIchemical entities of biological interestDPP-IVdipeptidyl peptidase IVDISCOtechdistance comparisonsHTVShigh throughput virtual screeningMDmolecular dynamicsMM-GBSAmolecular mechanics-generalized born surface areaOGTToral glucose tolerance testPBVSpharmacophore-based virtual screeningPDBprotein data bankRMSDroot mean square deviationROCreceiver operating characteristicsSPstandard precisionSBVSstructure-based virtual screeningVSvirtual screeningXPextra precisionCommunicated by Ramaswamy H. Sarma.

Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition.

Antimalarial drug resistance has emerged as a threat for treating malaria, generating a need to design and develop newer, more efficient antimalarial agents. This research aimed to identify novel leads as antimalarials. Dual receptor mechanism could be a good strategy to combat developing drug resistance. A series of benzimidazole acrylonitriles containing 18 compounds were designed, synthesized and evaluated for cytotoxicity, heme binding, ferriprotoporphyrin IX biomineralisation inhibition, and falcipain-2 enzyme assay. Furthermore, in silico docking and MD simulation studies were also performed.The tests revealed quite encouraging results. Three compounds, viz. R-01 (0.69 µM), R-04 (1.60 µM), and R-08 (1.61 µM), were found to have high antimalarial activity. These compounds were found to be in bearable cytotoxicity limits and their biological assay suggested that they had inhibitory activity against falcipain-2 and hemozoin formation. The docking revealed the binding mode of benzimidazole acrylonitrile derivatives and MD simulation studies revealed that the protein-ligand complex was stable. The agents exhibit good hemozoin formation inhibition activity and, hence, may be utilized as leads to design a newer drug class to overcome the drug resistance of hemozoin formation inhibitors such as chloroquine.