Discovery of small molecules through pharmacophore modeling, docking and molecular dynamics simulation against Plasmodium vivax Vivapain-3 (VP-3).

Vivapain-3(VP-3) protein is a family of cysteine rich proteases of malaria parasite is extensively reported to participate in a range of wide cellular processes including survival. VP-3 of plasmodium recognized as an attractive drug target in vector-borne diseases like malaria. In the present study we robust a homology model of VP-3 protein and generated the pharmacophore based models adapted to screen the best drug like compounds from PubChem database. Our results finds the fourteen best lead molecules were mapped with core pharmacophore features of VP-3 and top hits were further evaluated by molecular dynamics simulation and docking studies. Based on the molecular dynamics simulation and docking results and binding vicinity of ligand molecules, top five i.e., CID 74427945, CID 74427946, CID 360883, CID193721 and CID 51416859 showed the best docking scores with good molecular interactions against VP-3. Furthermore in silico ADMET and in vitro assays clearly exhibited that out of five three CID74427946, CID74427945 and CID360883 ligand molecules showed the best promising inhibition against VP-3. The present study believed to provide significant information of potential ligand inhibitors against VP-3 to design and develop the next generation malaria therapeutics through computational approach.

Novel 1, 4-dihydropyridines for L-type calcium channel as antagonists for cadmium toxicity.

The present study, we design and synthesize the novel dihydropyridine derivatives, i.e., 3 (a-e) and 5 (a-e) and evaluated, anticonvulsant activity. Initially due to the lacuna of LCC, we modeled the protein through modeller 9.15v and evaluated through servers. Docking studies were performed with the synthesized compounds and resulted two best compounds, i.e., 5a, 5e showed the best binding energies. The activity of intracellular Ca2+ measurements was performed on two cell lines: A7r5 (rat aortic smooth muscle cells) and SH-SY5Y (human neuroblastoma cells). The 5a and 5e compounds was showing the more specific activity on L-type calcium channels, i.e. A7r5 (IC50 = 0.18 ± 0.02 and 0.25 ± 0.63 µg/ml, respectively) (containing only L-type channels) than SH-SY5Y (i.e. both L-type and T-type channels) (IC50 = 8 ± 0.23 and 10 ± 0.18 µg/ml, respectively) with intracellular calcium mobility similar to amlodipine. Finally, both in silico and in vitro results exploring two derivatives 5a and 5e succeeded to treat cadmium toxicity.

Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats.

This study was aimed to examine the protective effects of supplementation with calcium + zinc (Ca + Zn) or vitamin E (Vit-E) on Cd-induced renal oxidative damage. Young albino Wistar rats (180 ± 10 g) (n = 6) control rats, Cd, Cd + Ca + Zn, and Cd + Vit-E experimental groups and the experimental period was 30 days. Rats were exposed to Cd (20 mg/kg body weight) alone treated as Cd treated group and the absence or presence of Ca + Zn (2 mg/kg each) or Vit-E (20 mg/kg body weight) supplementation treated as two separate groups. The activities of the stress marker enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and lipid peroxidase (LPx) were determined in renal mitochondrial fractions of experimental rats. We observed quantitative changes in SOD isoenzymatic patterns by non-denaturing PAGE analysis, and quantified band densities. These results showed that Cd exposure leads to decreases in SOD, CAT, GR, and GPx activities and a concomitant increase in LPx and GST activities. Ca + Zn and Vit-E administration with Cd significantly reversed Cd-induced perturbations in oxidative stress marker enzymes. However, Vit-E showed more inhibitory activity against Cd than did Ca + Zn, and it protected against Cd-induced nephrotoxicity.