Structure-Based Design of DevR Inhibitor Active against Nonreplicating Mycobacterium tuberculosis

Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organ ` isms. Our findings suggest that compound 10 ``locks'' DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.

Oxidation of bis-(2-hydroxy-1-naphthyl)methane with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. X-Ray crystal structure of a novel product

A novel compound obtained by the oxidation of the title compound with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone has been assigned structure (5) on the basis of spectral data and X-ray crystal structure analysis.

Structure of disodium deoxyuridine 5'-phosphate pentahydrate

Disodium deoxyuridine 5'-nhosDhate pentahvdrate, Na2(C9H l INEOsP). 5 H20, Call 11N208 P2-. 2Na +. 5 H20, crystallizes in the monoclinic space group P2: with a = 7.250 (4), b = 35.45 (2), c = 7.132 (4)/~, fl = 102.2 (4) °, Z = 4. The Cu Ka intensity data were collected photographically and estimated visually. The structure was obtained by the minimum-function method and difference syntheses and refined to an R of 0.089. In both molecules the uracil base has an anti conformation (2cN = 57.1 and 59.9 °) with respect to the sugar. The deoxyribose moiety of molecule B shows a typical C(l')-exo puckering, with C(I') displaced by 0.52 /k from the best plane. The furanose ring conformation of molecule A can be described as C(2')-endo,C(l')-exo. Both the molecules have an unusual trans-gauche conformation about the exocyclic C(4')-C(5') bond with (~0oo = 171.1, 172.2°; ~0oc = -64.7, -65.9°).

Conformational studies of the triphenylphosphazenyl side chain in cyclophosphazenes. II. Crystal and molecular structure of 2,4,4,6,6,8,8-heptachloro-2-triphenylphosphazenylcyclotetra(phosphazene), N4P4Cl7(NPPh3)

Abstract is not available.

Acoustic emission source location and damage detection in a metallic structure using a graph-theory-based geodesic pproach

A geodesic-based approach using Lamb waves is proposed to locate the acoustic emission (AE) source and damage in an isotropic metallic structure. In the case of the AE (passive) technique, the elastic waves take the shortest path from the source to the sensor array distributed in the structure. The geodesics are computed on the meshed surface of the structure using graph theory based on Dijkstra's algorithm. By propagating the waves in reverse virtually from these sensors along the geodesic path and by locating the first intersection point of these waves, one can get the AE source location. The same approach is extended for detection of damage in a structure. The wave response matrix of the given sensor configuration for the healthy and the damaged structure is obtained experimentally. The healthy and damage response matrix is compared and their difference gives the information about the reflection of waves from the damage. These waves are backpropagated from the sensors and the above method is used to locate the damage by finding the point where intersection of geodesics occurs. In this work, the geodesic approach is shown to be suitable to obtain a practicable source location solution in a more general set-up on any arbitrary surface containing finite discontinuities. Experiments were conducted on aluminum specimens of simple and complex geometry to validate this new method.

Structure and Function of Hemoglobin Confined Inside Silica Nanotubes

Investigations on the structure and function of hemoglobin (Hb) confined inside sol-gel template synthesized silica nanotubes (SNTs) have been discussed here. Immobilization of hemoglobin inside SNTs resulted in the enhancement of direct electron transfer during an electrochemical reaction. Extent of influence of nanoconfinement on protein activity is further probed via ligand binding and thermal stability studies. Electrochemical investigations show reversible binding of n-donor liquid ligands, such as pyridine and its derivatives, and predictive variation in their redox potentials suggests an absence of any adverse effect on the structure and function of Hb confined inside nanometer-sized channels of SNTs. Immobilization also resulted in enhanced thermal stability of Hb. The melting or denaturation temperature of Hb immobilized inside SNTs increase by approximately 4 degrees C as compared with that of free Hb in solution.