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by Sarang Kulkarni Anant and Ravi Hegde

The objective of this paper is to find a sequence of jobs in the flow shop to minimize makespan. A feed forward back propagation neural network is used to solve the problem. The network is trained with the optimal sequences of completely enumerated five, six and seven jobs, ten machine problem and this trained network is then used to solve the problem with greater number of jobs. The sequence obtained using artificial neural network (ANN) is given as the initial sequence to a heuristic proposed by Suliman and also to genetic algorithm (GA) as one of the sequences of the population for further improvement. The approaches are referred as ANN-Suliman heuristic and ANN-GA heuristic respectively. Makespan of the sequences obtained by these heuristics are compared with the makespan of the sequences obtained using the heuristic proposed by Nawaz, Enscore and Ham (NEH) and Suliman Heuristic initialized with Campbell Dudek and Smith (CDS) heuristic called as CDS-Suliman approach. It is found that the ANN-GA and ANN-Suliman heuristic approaches perform better than NEH and CDS-Suliman heuristics for the problems considered.

Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 microM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 microM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 microM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr) variants with EC50s of 0.027 to 0.089 microM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of0.26 microM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 microM [HIV216-0.16 microM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 microM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr.

The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.

Altered microtubule (MT) stability prior to neurite extension was examined in P19 embryonal carcinoma cells induced to differentiate along the neural pathway by retinoic acid. In undifferentiated P19 cells few acetylated MTs were detected by immunofluorescence staining and these were resistant to disassembly by colchicine at 1 $\mu$g/mL for 45 minutes. Twenty-four hours after neural induction there was an increase in the number of acetylated MTs and in the number of MTs that were resistant to colchicine treatment. This suggested that the MT array in undifferentiated cells is initially dynamic and becomes less dynamic during early neural differentiation prior to morphogenesis. Quantitative immunoblotting showed no change in the levels of total tubulin, but a two-fold increase in the relative level of acetylated tubulin was detected. MT turnover in P19 cells was then examined directly by microinjecting biotin-conjugated bovine brain tubulin. Computer-aided silicon intensified target camera (SIT) imaging of biotin-tubulin incorporation into the MT array showed that by 30 minutes, 92.4 $\pm$ 3.02% of total MTs turned over in undifferentiated cells. In contrast, in the retinoic acid-induced cells 52.8 $\pm$ 19.37% of the MT array turned over in 30 minutes. In conclusion, there are changes in colchicine stability and in tubulin acetylation that are correlated with changes in MT dynamics occurring prior to neurite outgrowth.