2D QSAR Studies of Several Potent Aminopyridine, Anilinopyrimidine and Pyridine Carboxamide-based JNK Inhibitors.

The c-Jan N-terminal kinases are members of the mitogen activated protein kinase family of signaling proteins. Amino pyridine based compounds, 4-anilino pyrimidine derivatives, and 2-pyridine carboxamide derivatives have been identified as potent JNK inhibitors with good cellular activity. In this study we calculated molecular topological and quantum chemical descriptors of 15 training compounds and three quantitative structure activity relationships models have been constructed. The significance of three models is judged on the basis of correlation, Fischer F test and quality factor (Q). This study is helpful for screening potent inhibitors of protein kinases.

Comparative analysis of codon usage patterns and identification of predicted highly expressed genes in five Salmonella genomes.

PURPOSE: To analyse codon usage patterns of five complete genomes of Salmonella , predict highly expressed genes, examine horizontally transferred pathogenicity-related genes to detect their presence in the strains, and scrutinize the nature of highly expressed genes to infer upon their lifestyle. METHODS: Protein coding genes, ribosomal protein genes, and pathogenicity-related genes were analysed with Codon W and CAI (codon adaptation index) Calculator. RESULTS: Translational efficiency plays a role in codon usage variation in Salmonella genes. Low bias was noticed in most of the genes. GC3 (guanine cytosine at third position) composition does not influence codon usage variation in the genes of these Salmonella strains. Among the cluster of orthologous groups (COGs), translation, ribosomal structure biogenesis [J], and energy production and conversion [C] contained the highest number of potentially highly expressed (PHX) genes. Correspondence analysis reveals the conserved nature of the genes. Highly expressed genes were detected. CONCLUSIONS: Selection for translational efficiency is the major source of variation of codon usage in the genes of Salmonella . Evolution of pathogenicity-related genes as a unit suggests their ability to infect and exist as a pathogen. Presence of a lot of PHX genes in the information and storage-processing category of COGs indicated their lifestyle and revealed that they were not subjected to genome reduction.

A fluorescence spectroscopic and molecular dynamics study of bis-ANS/protein interaction.

Despite emergence of bis-ANS as a major fluorescence probe of proteins structure, conformational and spectroscopic properties of protein/bis-ANS complexes remains largely unexplored. We have shown that fluorescence polarization of both ANS and bis-ANS is excitation wavelength dependent and this is a property of all protein-ANS/bis-ANS complexes studied. Bis-ANS excitation maximum is always more red shifted than the corresponding ANS complex. Even when corrected for the red shift, the bis-ANS complexes in some, but not all, cases show only a little lowering of polarization, suggesting modest additional depolarization in bis-ANS compared to ANS. Calculation of energy migration rate between the two rings suggests that energy migration rate should be high at all values of the naphthyl-naphthyl dihedral angle. Although, Molecular mechanics and dynamics calculations show that the lowest energy conformation of bis-ANS is when the two naphthalene rings are roughly perpendicular to each other, due to rapid energy migration this conformation should lead to dramatic lowering of emission anisotropy, unlike what is observed. Salt and temperature dependence of bis-ANS/protein interaction suggests little ionic interaction and pre-dominant interaction through hydrophobic aromatic rings. We conclude that bis-ANS binds to proteins through interaction with the aromatic rings and with two rings nearly parallel to each other.

Molecular dynamics simulation of colchicinoids.

Colchicine, a tricyclic alkaloid, has a remarkable range of biological activities. It binds with tubulin and prevents the formation of microtubules. This compound consists of a six membered aromatic ring (A ring), a seven membered troponoid ring (C ring) and another seven membered aliphatic ring (B ring). Using molecular mechanics and molecular dynamics simulations as tools, conformational analysis of colchicine and its several important analogs were done. Molecular mechanics studies show that conformational space of these molecules have one low energy region. Taking the low energy minima as the starting conformation, molecular dynamics simulation for 100 pico seconds is done for each of the analogs and molecular dynamics simulation in solution is done for three representative compounds colchicine,isocolchicine and A-C compound. Internal coordinate trajectories show that the value of the dihedral angle C9-C7-C1-C14 (phi), (C7-C1 bond connects the A and C ring), is within 40 degrees to 50 degrees for all the compounds with fluctuations less than 15 degrees. These calculations indicate that there is an overall similarity in the dynamically averaged structure of all the drugs. The A ring and B ring of the compounds are more or less rigid. The C ring is somewhat flexible, the average conformation and motional properties show overall similarity. The potential energy curve and dynamics behaviour of colchicine and isocolchicine suggests that the difference in binding property of colchine and isocolchicine may originate from the positional difference of carbonyl oxygen and methoxy group of C ring, which is the only difference in the structures of the two compounds and this has no effect on the motional property and average conformations of these two compounds. From our study it is proposed that the movements occuring at various positions of the drug molecules are significantly correlated. It is suggested that such correlated motion may play an important role in the biological property of these compounds.

Role of zinc in tRNA-acceptor stem binding by glutamyl-tRNA synthetase from E.coli: a molecular modeling study.

A model of the N-terminal half of glutamyl-tRNA synthetase from E. coli was constructed on the basis of similarity in sequence and function of Glutaminyl- and Glutamyl-tRNA synthetases. The glutaminyl-tRNA synthetase does not contain any zinc atom, but glutamyl-tRNA synthetase from E. coli contains one atom of zinc. The specific role of zinc is not yet known. In this article, molecular modeling is employed to show that the zinc atom is well outside the contact region of the acceptor stem of tRNA. The placement of a zinc atom at a significant distance from the tRNA acceptor stem indicates that the role of zinc is likely to be indirect and structural.