Computational binding mechanism of Mycobacterium tuberculosis UDP-NAG enolpyruvyl transferase (MurA) with inhibitors fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic aci

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and about two million deaths are attributable to TB annually. The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. In this work, 3D structural model of Mtb-MurA enzyme has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. substrate binding pocket, and common docking site. Multiple sequence alignment and 3D structure model provided the putative substrate binding pocket of Mtb-MurA with respect to E.coli MurA. This analysis was helpful in identifying the binding sites and molecular function of the MurA homologue. Molecular docking study was performed on this 3D structural model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5-sulfonoxyanthranilic acid derivatives is showed best interaction compared with other inhibitor, taking in to this we also design a new efficient analogs of T6361 and T6362 which are showed even better interaction with Mtb-MurA than the parental5-sulfonoxy-anthranilic acid derivatives. Further the comparative molecular electrostatic potential and cavity depth analysis of Mtb-MurA suggested several important differences in its substrate and inhibitor binding pocket. Such differences could be exploited in the future for designing of a more specific inhibitor for Mtb-MurA enzym

Study of Dengue virus E proteingene of clinical isolates of Andhra Pradesh: in the contest to Epidemiological features

In this current article, we showed the dengue virus serotype 2 protein E gene from the clinical samples of Andhra Pradesh in an acute phase infection. The models showed positive for the protein E gene with RT-PCR techniques and cellular isolates. Two unique sequences are identified with new substrains, which are similar to the hermits of the earlier reports. This study provided the epidemiology insight of the isolated strain through the phylogenetic analyses

Synthesis, spectroscopic studies of novel N-substituted phthalimides and evaluation of their antibacterial, antioxidant, DNA binding and molecular docking studies

A new series of N-substituted phthalimide derivatives were prepared by condensation of appropriate amount of n-amino tetrachlorophthalimide with respective aldehyde in glacial acetic acid. The structural investigation of the synthesized compounds was done by spectroscopic methods (UV-Vis., IR, 1H and 13C NMR) and elemental analysis. The antibacterial screening of these compounds was performed against Escherichia coli and Staphylococcus mutans. The synthesized compounds were evaluated for their antioxidant potential using 2,2-diphenyl-1-picrylhydrazyl (DPPH) as a scavenging agent. The interaction ability of most promising compounds (3a and 3b) with native calf thymus DNA (Ct-DNA) was also studied by means of UV-Vis., circular dichroism (CD), viscosity measurements and thermal studies. The intrinsic binding constants (Kb) of 3a and 3b with Ct-DNA obtained from UV-Vis. absorption studies were 8 × 104 and 1 × 105, respectively. Molecular docking of target compounds (3a and 3b) against DNA dodecamer d(CGCGAATTCGCG)2 has been carried out. The test compounds exhibited remarkable antibacterial, antioxidant and DNA binding activities.

Clinical isolates of Anantapuramu for the protein E isolation of the dengue virus

In theclinical samples from the state of Anantapuramu, the dengue virus serotype 2 protein E gene was found. It was established that the protein E gene was present in the models by using RT-PCR and cellular isolates. There has been one new sub strain discovered that are akin to the hermits described in previous investigations. An investigation of the epidemiology of the isolated strain was conducted using a phylogenetic analysis of the strain

DESIGNING AND EVALUATION OF DICLOFENAC SODIUM SUSTAINED RELEASE MATRIX TABLETS USING HIBISCUS ROSA-SINENSIS LEAVES MUCILAGE

ABSTRACT The main objective of the present investigation was to design matrix tablets of Diclofenac sodium using Hibiscus rosa-sinensis leaves mucilage and to study its release retardant activity in prepared sustained release formulations. Hibiscus rosa-sinensis leaves were evaluated for physicochemical properties. Different matrix tablets of Diclofenac sodium Hibiscus rosa-sinensis leaves mucilage were formulated. The matrix tablets found to have better uniformity of weight, hardness, friability and drug content with low deviated values. The swelling behavior, release rate characteristics and the in-vitro dissolution study proved that the dried Hibiscus rosa-sinensis leaves mucilage can be used as a matrix forming material for preparing sustained release matrix tablets. The kinetics of drug release from selected DHR-5 formulation followed zero order. It was concluded that Hibiscus rosa-sinensis leaves mucilage can be used as an effective matrix forming polymer, to sustain the release of Diclofenac sodium from the formulation

Prediction of Evolutionarily important catalytic amino acid of Mycobacterium tuberculosis O-Succinylbenzoate synthase through in silico mutational analysis

The emergence of tuberculosis resistant to multiple, first- and second-line antibiotics poses challenges to a global control strategy that relies on standard drug treatment regimens. The high drug-resistant strains of Mycobacterium tuberculosis (Mtb) have been implicated in outbreaks and have been found throughout the world; a comprehensive understanding, the magnitude of this threat requires an accurate assessment of the worldwide burden of resistance. In an attempt to design anti-TB drugs, the target chosen is a key enzyme of Mtb, O-Succinylbenzoate synthase (OSBS), which is an attractive target for its role in electron transport chain as OSBS is not available in humans. An attempt has been to built the 3-D structure of Mtb-OSBS using online Swiss model server. With sequence alignment and scan motif identification, the importance of evolutionarily significant residues that are of functional importance for ligand binding and that form active sites were well established. Molecular simulation calculations of Mtb-OSBS model indicated evolutionarily conserve residues (Lys110 and Lys212) are the best in molecular interaction with substrate 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC). The in silico mutational analysis of Mtb-OSBS model showed the evolutionarily conserved residues that are essential for catalytic activity. It has been found that active site amino acids of Mtb-OSBS are very important to maintain activity of the enzyme, which provides a novel approach to design new pharmacophore SHCHC substrate analogs against Mtb-OSBS. A series of SHCHC substrate analogs (1–100) compounds have been docked with the amino acid residues at the active site of the Mtb-OSBS enzyme, using AutoDock 4.0, a program employed to perform automated molecular docking. The free energies of binding (∆G) and inhibition constants (Ki) of the docked compounds were calculated by the Lamarckian Genetic Algorithm (LGA). Excellent to good correlations between the calculated and experimental Ki values were reported