Increasing incidence of artemisin resistance endangers very foundations of current guideline based antimalarial therapy. There is an unmet need to develop newer strategies, targeting novel pathophysiology to set high standards in antimalaria care. Of late, the antimalarial drug pipeline is becoming increasingly robust, and promises healthier outcomes. We discuss few drugs currently under pre-clinical development that have shown encouraging results.

Inter-individual differences in drug action and side-effects have given rise to various types of metabolic screening techniques in drug development. They range from in-vitro, in-vivo techniques to sophisticated in-silico techniques. While validation of most systems is still largely pending, such techniques offer predicting various characteristics of drugs, namely metabolic stability, consequent half-life, dosage schedule, or induction potential. The techniques are getting refined everyday which offers better avenues of research and drug development. We discuss in brief latest metabolic screening techniques currently in use.

The nitric oxide (NO) synthesized by neuronal nitric oxide synthase (nNOS) acts as a neurotransmitter and plays a crucial role in a series of neurobiological functions. In diseased condition, activated nNOS induces nitrosylation as well as phosphorylation of tau protein and glycogen synthase kinase 3 beta (GSK-3β) respectively. Hyper phosphorylation of tau accelerates tau oligomerization resulting in formation of neurofibrillary tangles (NFT), ensuring the neuronal cell death in hippocampus region; a hallmark of Alzheimer's disease (AD). Thus, designing inhibitor towards nNOS may reduce the neuronal loss caused by nNOS. Hence nNOS has been one of the revitalizing targets for AD. In the present work, one energetically optimized structure-based pharmacophore (e-pharmacophore) was generated using nNOS co-crystal structure (4D1N) to map important pharmacophoric features of nNOS. Shape based similarity screening performed using e-pharmacophore against in-house library of more than one million compounds resulted 2701 library of compounds. Rigid receptor docking (RRD) was applied and followed by molecular mechanics and generalized Born and surface area (MM-GBSA) calculation which results 22 nNOS ligands. To define the leads, dock complexes were subjected to quantum-polarized ligand docking (QPLD) followed by free energy calculations revealed 3 leads. On comparison with 1 existing inhibitor,it concealed three best leads with lower binding energy and better binding affinity. The best lead was subjected to induced fit docking (IFD) with MM-GBSA calculation and further molecular dynamics (MD) simulations for 50 ns in solvated model system. Potential energy, root mean square deviation (RMSD) and root mean square fluctuations (RMSF) results disclosed constancy of lead 1 interactions throughout 50 ns MD simulations run. Thus proposed three leads are having favorable absorption distribution metabolism excretion toxicity (ADME/T) properties and provide a scaffold for designing nNOS antagonists.

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Grace et al.: Therapeutic Effect of Nano-formulated 9-cis-Retinoic acidThe main objective of the present work was to develop liposomal nano-formulation for 9-cis-retinoic acid using di-stearoylphosphocholin/cholesterol mixture, to characterise and to evaluate its anticancer effect on A549 human lung cancer cell lines. The liposomes were prepared using thin film formulation method and characterization of particle size and shape were carried out employing dynamic light scattering and scanning electron microscopy techniques, respectively. The level of drug entrapment into the liposomes and liposomal stability were analysed using spectrophotometry and expressed in terms of percent entrapment. The level of 9-cis-retinoic acid in treated cells also was assayed using spectrophotometry. In vitro drug release level evaluated using a dialysis bag. The anticancer effect was studied using MTT and trypsin blue assays in human lung cancer cell line. The drug entrapment level achieved was 83.33 %. Viability of cancer cells was significantly reduced after liposomal 9-cis-retinoic acid treatment. From these results it could be concluded that the liposomal 9-cis-retinoic acid was easily taken up by the A549 cells compared to free 9-cis-retinoic acid, which might have enhanced the anticancer activity observed in this study.