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.

Sivaranjani et al.: Antimycobacterial Therapeutic Design against Shikimate Pathway In Mycobacterium tuberculosis, shikimate pathway is essential for amino acid biosynthesis, siderophores formation to overcome starvation, to survive in low oxygen conditions as well as for pathogen's virulence and growth. 3-Dehydroquinate synthase of Mycobacterium tuberculosis plays a vital role in the biosynthesis of aromatic amino acids and various secondary metabolites through shikimate pathway and is responsible for development of drug resistance. Thus, designing inhibitors towards this attractive drug target 3-dehydroquinate synthase to inhibit the synthesis of aromatic amino acids and essential secondary metabolites could prevent survival of this pathogen. In the present work, docking studies were performed using the 3-dehydroquinate synthase crystal structure against 1082 approved DrugBank compounds. The best DrugBank compound and substrate analogue (carbaphosphonate) were subjected to shape screening against 21 million compounds and resulted compounds constituted the AroB ligand-dataset. The library was subjected to rigid receptor docking, quantum polarized ligand docking, and induced fi t docking followed by molecular mechanics-generalized born and surface area calculations resulted in two compounds possess the best scoring functions (XP GScore). Molecular dynamics simulations (50 ns) in the solvated model system determined consistency nature of AroB-lead 1 over the AroB-carbaphosphonate complex. Moreover, upon comparison of the proposed leads with the best DrugBank compound and carbaphosphonate, the leads showed favourable absorption, distribution, metabolism, excretion and toxicity properties within the range of 95 % FDA approved drugs, and showing better antagonist properties than the existing inhibitors. Hence these leads were proposed as novel inhibitors against tuberculosis.