Computational Design of Novel Allosteric Inhibitors for Plasmodium falciparum DegP

The serine protease, DegP exhibits proteolytic and chaperone activities, essential for cellular protein quality control and normal cell development in eukaryotes. The P. falciparum DegP is essential for the parasite survival and required to combat the oscillating thermal stress conditions during the infection, protein quality checks and protein homeostasis in the extra-cytoplasmic compartments, thereby establishing it as a potential target for drug development against malaria. Previous studies have shown that diisopropyl fluorophosphate (DFP) and the peptide SPMFKGV inhibit E. coli DegP protease activity. To identify novel potential inhibitors specific to PfDegP allosteric and the catalytic binding sites, we performed a high throughput in silico screening using Malaria Box, Pathogen Box, Maybridge library, ChEMBL library and the library of FDA approved compounds. The screening helped identify five best binders that showed high affinity to PfDegP allosteric (T0873, T2823, T2801, {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, CD00811) and the catalytic binding site (T0078L, T1524, T2328, BTB11534 and 552691). Further, molecular dynamics simulation analysis revealed {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, BTB11534 as the best hits forming a stable complex. WaterMap and electrostatic complementarity were used to evaluate the novel bio-isosteric chemotypes of {"type":"entrez-protein","attrs":{"text":"RJC02337","term_id":"1480409465","term_text":"RJC02337"}}RJC02337, that led to the identification of 231 chemotypes that exhibited better binding affinity. Further analysis of the top 5 chemotypes, based on better binding affinity, revealed that the addition of electron donors like nitrogen and sulphur to the side chains of butanoate group are more favoured than the backbone of butanoate group. In a nutshell, the present study helps identify novel, potent and Plasmodium specific inhibitors, using high throughput in silico screening and bio-isosteric replacement, which may be experimentally validated.     

Thermal studies of some aryloxides of titanium(IV)

Thermal behaviour of aryloxides of titanium(IV) of composition TiCl_n(OAr)_4?n (wheren=0→3 and OAr=OC₆Bu^t-4, OC₆H₄OMe-4 and OC₆H₂-Bu ₂ ^t -2,6?Me-4) has been studied by DTA and TG analysis. Multiple decomposition steps have been indicated by thermal weight losses which are both exothermic and endothermic as shown by DTA curves. Based upon the total % loss in weight; during entire decomposition titanium dioxide has been found to be the final residue in each case.     

4-t-Butylphenoxo complexes of oxovanadium(V)

Summary Complexes of composition [VOCl₂(OC₆H₄Bu-t-4)] (1) and [VOCl(OC₆H₄Bu-t-4)₂] (2) have been synthesized by the reaction of VOCl₃ with equimolar and bimolar amounts, respectively, of 4-t-BuC₆H₄OSiMe₃ in CCl₄ and characterized by physio-chemical techniques. The complexes react with -hydroxyaldehydes and ketones such as 2-hydroxybenzaldehyde (salicylaldehyde, salH), and 2-hydroxy-2-phenylacetophenone (benzoin, benzH), 2-hydroxyacetophenone (hapH) and also with the potassium salt of p-chlorobenzohydroxamic acid (KBHACl) in 11 and 12 molar ratios, to yield five- and six-coordinate complexes.     

Influence of preferential solvation on the interpolymer complex formation between methacrylic acid–methacrylamide copolymer and poly(vinyl pyrrolidone)

Interpolymer complex formation has been studied between methacrylic acid–methacrylamide copolymer and poly(vinyl pyrrolidone) in acetone–water mixtures of different compositions. At a specific composition of the solvent (e.g., 70% water + 30% acetone by volume), the intrinsic viscosity of the copolymer and the reduced viscosity of 1:1 interpolymer complex had minimum values. Preferential solvation coefficients (λ/C) have been calculated for the various compositions of the solvent mixtures. An excellent coincidence could be obtained between the maximum (λ/C) and the minimum in the viscosity of the polymer solutions. Interpretations have been sought in terms of conformational change of the copolymer at the specific composition of the solvent mixture.     

Theoretical study on the structure and property relationship of the cationic conjugated polyelectrolytes

A theoretical study using density functional theory was performed to understand the structure/property relationship of the cationic conjugated polyelectrolytes, poly[9,9-bis-(6′-N,N,N-trimethylammonium) hexyl] fluorene-alt-4,7-(2,1,3-benzothiadiazole)] (PFBT-X, where X = Br). The torsion angle between the fluorene and benzothiadiazole units in the PFBT monomer was found to substantially affect the structural and electronic properties of the cationic PFBT monomer. The changes of geometrical parameter, HOMO and LUMO energy levels, and band gap, as well as the absorption maximum are discussed in terms of the torsion in the PFBT monomer structure. For comparison, its neutral analogue, the monomer of poly(9,9-di-n-octylfluorene-alt-benzothiadiazole) (F8BT) was also studied. The length of conjugation backbone was also examined.     

Solution properties of poly p-isopropyl α-methylstyrene

Two series (S and F) of poly p-isopropyl α-methylstyrene were characterized by viscometry, light scattering (LS), osmometry and gel permeation chromatography (GPC). S-samples were prepared by bulk anionic polymerization whereas F-samples were obtained on fractionation by preparative GPC of a polymer also prepared in bulk but with a different initiator. The K parameter in the Mark-Houwink relation was 5.55 × 10^?4 for series-S and 4.50 × 10^?4 for series-F, whereas the exponent a was 0.55 for both series. The Mark-Houwink equations for series-S and -F hold good at 25 and 30° for both toluene and tetrahydrofuran as solvents and have been corrected for polydispersity. The chain dimensions obtained with LS were much higher than those computed from the viscosity data indicating that the hydrodynamic theories in their present state should not be used for the calculation of chain dimensions. The deviations from the GPC universal calibration curve of polystyrene observed with some samples were attributed to structural differences among the polymers and to their high polydispersity.     

Determination of critical micelle concentration by hyper-rayleigh scattering

The critical micelle concentration (CMC) of several surfactants that contain an NLO chromophore, either at the hydrocarbon tail, or at the hydrophilic headgroup, or even as a counterion, was determined by hyper-Rayleigh scattering (HRS). In all cases, the HRS signal exhibited a similar variation with surfactant concentration, wherein the CMC is inferred from a rather unprecedented drop in the signal intensity. This drop is attributed to the formation of small pre-micellar aggregates, whose concentrations become negligible above CMC. In addition, a probe molecule, which upon protonation yielded a species with significantly enhanced HRS intensity, was developed and its utility for the determination of the CMC of simple fatty acids was demonstrated.     

Thermal conductivity of C60 and C70 crystals

We have performed thermal conductivity measurements on C₆₀ and C₇₀ crystals grown by sublimation. For single crystal C₆₀, the thermal conductivity k is 0.4 W/m K at room temperature and is nearly temperature independent down to 260K. We observed a sharp orientational phase transition at 260K, indicated by a 25% jump in k. Below 90K, k is time dependent, which manifests itself as a shoulder-like structure at 85K. The temperature and time dependence of k below 260K can be described by a simple model which accounts for the thermally activated hopping of C₆₀ molecules between two nearly degenerate orientations, separated by an energy barrier of 240 meV. It is found that solvents have a strong influence on the physical properties of C₇₀ crystals. For solvent-free C₇₀ crystal, k is about constant above 300K. There is a broad first-order phase transition in k at 300K with a 25% jump. We associate this transition with the aligning of the fivefold axes of the C₇₀ molecules along the c-axis of the hexagonal lattice. Upon further cooling, k increases and is time independent.