Molecular Surface Features in Modeling the HIV-1 RT Inhibitory Activity of 2-(2,6-Disubstituted phenyl)-3-(substituted pyrimidin-2-yl)-thiazolidin-4-ones

The human immunodeficiency virus-1 reverse transcriptase inhibitory activity of 2-(2,6-disubstituted phenyl)-3-(substituted pyrimidin-2-yl)-thiazolidin-4-ones have been analyzed using combinatorial protocol in multiple linear regression (CP-MLR) with several electronic and molecular surface area features of the compounds obtained from Molecular Operating Environment (MOE) software. The study has indicated the role of different charged molecular surface areas in modeling the inhibitory activity of the compounds. The derived models collectively suggested that the compounds should be compact without bulky substitutions on its peripheries for better HIV-1 RT inhibitory activity. It also emphasized the necessity of hydrophobicity and compact structural features for their activity. The scope of the descriptors identified for these analogues have been verified by extending the dataset with different 2-(disubstituted phenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones. The joint analysis of extended dataset highlighted the information content of identified descriptors in modeling the HIV-1 RT inhibitory activity of the compounds.

CP-MLR Directed QSAR Studies on the Antimycobacterial Activity of Functionalised Alkenols - Topological Descriptors in Modeling the Activity

The antimycobacterial activity of nitro/ acetamido alkenol derivatives and chloro/ amino alkenol derivatives has been analyzed through combinatorial protocol in multiple linear regression (CP-MLR) using different topological descriptors obtained from Dragon software. Among the topological descriptor classes considered in the study, the activity is correlated with simple topological descriptors (TOPO) and more complex 2D autocorrelation descriptors (2DAUTO). In model building the descriptors from other classes, that is, empirical, constitutional, molecular walk counts, modified Burden eigenvalues and Galvez topological charge indices have made secondary contribution in association with TOPO and / or 2DAUTO classes. The structure-activity correlations obtained with the TOPO descriptors suggest that less branched and saturated structural templates would be better for the activity. For both the series of compounds, in 2DAUTO the activity has been correlated to the descriptors having mass, volume and/ or polarizability as weighting component. In these two series of compounds, however, the regression coefficients of the descriptors have opposite arithmetic signs with respect to one another. Outwardly these two series of compounds appear very similar. But in terms of activity they belong to different segments of descriptor-activity profiles. This difference in the activity of these two series of compounds may be mainly due to the spacing difference between the C1 (also C6) substituents and rest of the functional groups in them.

Topological Descriptors in Modeling the HIV Inhibitory Activity of 2-Aryl-3-pyridyl-thiazolidin-4-ones

The HIV-1 RT inhibitory activity of 2-(2,6-dihalophenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones has been analyzed with different topological descriptors obtained from DRAGON software. Here, simple topological descriptors (TOPO), Galvez topological charge indices (GVZ) and 2D autocorrelation descriptors (2DAUTO) have been found to yield good predictive models for the activity of these compounds. The correlations obtained from the TOPO class descriptors suggest that less extended or compact saturated structural templates would be better for the activity. The participating GVZ class descriptors suggest that they have same degree of influence on the activity. In 2DAUTO class, the large participation of descriptors of lags seven and three indicate the association of activity information with the seven and three centered structural fragments of these compounds. The physicochemical weighting components of these descriptors suggest homogeneous influence of mass, volume, electronegativity and/ or polarizability on the activity.

Reductase inhibitory activity of some flavones: Topological descriptors in modeling the activity

In healthy people, glucose is metabolized through Embden-Meyerhoff pathway. In cases of diabetes mellitus, with the increased levels of glucose in insulin-insensitive tissues the Aldose Reductase (AR) in polyol pathway facilitates the conversion of glucose to sorbitol. In this cascade of events the accumulated sorbitol is attributed to be responsible for cataract, neuropathy and retinopathy in diabetic cases.1,2 Thus, the inhibition of AR in polyol pathway may prevent and lead to the cure of the complications arising out of the diabetes mellitus. In this background, Matsuda and coworkers3 studied the AR inhibitory activity of large number of flavones and related compounds from traditional antidiabetic remedies. Here, many of these compounds shared 2-Aryl-benzpyran-4-one as scaffold for different chemical groups surrounding this moiety. This offers scope to investigate the AR inhibitory activity of these compounds in relation to the functional group environment surrounding this core

Topological Descriptors in Modeling the Antimalarial Activity of 4-(3’, 5’-Disubstitutedanilino)quinolines

Two series of closely related antimalarial agents, 7-chloro-4-(3’,5’-disubstitutedanilino) quinolines, have been analyzed using Combinatorial Protocol in Multiple Linear Regression (CP-MLR) for the structure-activity relations with more than 450 topological descriptors for each set. The study clearly suggested that 3’- and 5’- substituents of the anilino moiety map different domains in the activity space. While one domain favors the compact structural frames having aromatic, heterocyclic ring(s) substituted with closely spaced F, NO2 and O functional groups, the other prefers structural frames enriched with unsaturation, loops, branches, electronic content and devoid of carbonyl function. Also, this study gives an indication in favour of the electron rich centres in the aniline substituent groups for better antimalarial activity; an observation in line with several of the previous reports too. The models developed and the participating descriptors suggest that the substituent groups of the 4-anilino moiety of the 4-(3’, 5’-disubstitutedanilino)quinolines hold scope for further modification in the optimisation of the antimalarial activity.

C-3 Alkyl /Arylalkyl-2,3-dideoxy hex-2-enopyranosides as Antitubercular Agents: Synthesis, Biological Evaluation and QSAR Study

A series of C-3 alkyl and arylalky 2,3-dideoxy hex-2-enopyranoside derivatives were synthesized by Morita-Baylis-Hillman reaction using enulosides 4, 5 and 6 and various aliphatic and aromatic aldehydes. The compounds were evaluated in vitro for the complete inhibition of growth of Mycobacterium tuberculosis H37Rv. They exhibited moderate to good activity in the range of 25-1.56 µg/mL. Among these, 4d, 4h, 5c and 4hr showed activity at minimum inhibitory concentrations, 3.12, 6.25, 1.56 and 1.56µg/mL, respectively. These compounds were safe against cytotoxicity in VERO cell line and mouse macrophage cell line J 744A.1. A QSAR analysis by CP-MLR with alignment-free 3D-descriptors indicated the relevance of structure space comparable to the minimum energy conformation (from conformational analysis) of 5c to the activity. The study indicates that the compounds attaining conformational space 5c and reflecting some symmetry, minimum eccentricity and closely placed geometric and electronegativity centers therein are favorable for activity.

A Model to quantify Disease state based on the ayurvedic concept of Tridosa

The ancient Indian system of Ayurveda revolves around the concept of tridosha namely vata, pitta and kapha. The disturbance in the steady state of these three factors is said to be the starting point of the development of diseases. Even though the diseases and their associated symptoms are well- described in the medical system, no mention is directly made in the basic texts about the quantification. We offer here a specific protocol to quantify a disease in terms of ayurvedic principles

A Simple Algorithm for Unique Representation of Chemical Structures - Cyclic/ Acyclic Functionalized Achiral Hydrocarbons

An algorithm, based on ‘vertex priority values’ has been proposed to uniquely sequence and represent connectivity matrix of chemical structures of cyclic/ acyclic functionalized achiral hydrocarbons and their derivatives. In this method ‘vertex priority values’ have been assigned in terms of atomic weights, subgraph lengths, loops, and heteroatom contents. Subsequently the terminal vertices have been considered upon completing the sequencing of the core vertices. This approach provides a multilayered connectivity graph, which can be put to use in comparing two or more structures or parts thereof for any given purpose. Furthermore the basic vertex connection tables generated here are useful in the computation of characteristic matrices/ topological indices, automorphism groups, and in storing, sorting and retrieving of chemical structures from databases.

QSAR Studies on Thiazolidines: A Biologically Privileged Scaffold

A large number of drugs and biologically relevant molecules contain heterocyclic systems. Often the presence of hetero atoms or groupings imparts preferential specificities in their biological responses. Amongst the heterocyclic systems, thiazolidine is a biologically important scaffold known to be associated with several biological activities. Some of the prominent biological responses attributed to this skeleton are antiviral, antibacterial, antifungal, antihistaminic, hypoglycemic, anti-inflammatory activities. This diversity in the biological response profiles of thiazolidine has attracted the attention of many researchers to explore this skeleton to its multiple potential against several activities. Many of these synthetic and biological explorations have been subsequently analyzed in detailed quantitative structure-activity relationship (QSAR) studies to correlate the respective structural features and physicochemical properties with the activities to identify the important structural components in deciding their activity behavior. In this, drugs or any biologically active molecules may be viewed as structural frames consisting of strategically positioned functional groups that will interact effectively with the complementary groups/sites of the receptor. With this in focus, the present article reviews the QSAR studies of diverse biological activities of the thiazolidines published during the past decade.

Is body mass index associated with Barrett esophagus: A systematic literature review

Background. Risk factors underlying the development of Barrett's esophagus (BE) are poorly understood. Recent studies have examined the association between elevated body mass index (BMI) and BE with conflicting results. A systematic review of literature was performed to study this association.^ Methods. Cross-sectional, case control and cohort studies published through April 2007 meeting strict inclusion and exclusion criteria were included. A thorough data abstraction, including that of reported crude or adjusted odds ratios or mean BMI, was performed. Crude odds ratios were estimated from available information in 3 studies.^ Results. Of 630 publications identified by our search items, 59 were reviewed in detail and 12 included in the final analyses. 3 studies showed a statistically significant association between obesity and BE (30-32) while 2 studies found a statistically significant association between overweight and BE (31, 32). Two studies that reported BMI as a continuous variable found BMI in cases to be significantly higher than that in the comparison group (30, 32). Other studies failed to show an significant association between elevated BMI and BE.^ Conclusions. There is conflicting data regarding the association between elevated BMI and BE. It is important to identify other risk factors that in combination with elevated BMI may lead to BE. Further studies are needed to evaluate if the presence of reflux symptoms or any particular pattern of obesity, are independently associated with BE.^ Key words. Barrett's esophagus, obesity, Body Mass Index, gastroesophageal reflux disease, meta-analysis^

A canonical UTD solution for electromagnetic scattering by an electrically large impedance circular cylinder illuminated by an obliquely incident plane wave

A uniform geometrical theory of diffraction (UTD) solution is developed for the canonical problem of the electromagnetic (EM) scattering by an electrically large circular cylinder with a uniform impedance boundary condition (IBC), when it is illuminated by an obliquely incident high frequency plane wave. A solution to this canonical problem is first constructed in terms of an exact formulation involving a radially propagating eigenfunction expansion. The latter is converted into a circumferentially propagating eigenfunction expansion suited for large cylinders, via the Watson transform, which is expressed as an integral that is subsequently evaluated asymptotically, for high frequencies, in a uniform manner. The resulting solution is then expressed in the desired UTD ray form. This solution is uniform in the sense that it has the important property that it remains continuous across the transition region on either side of the surface shadow boundary. Outside the shadow boundary transition region it recovers the purely ray optical incident and reflected ray fields on the deep lit side of the shadow boundary and to the modal surface diffracted ray fields on the deep shadow side. The scattered field is seen to have a cross-polarized component due to the coupling between the TEz and TMz waves (where z is the cylinder axis) resulting from the IBC. Such cross-polarization vanishes for normal incidence on the cylinder, and also in the deep lit region for oblique incidence where it properly reduces to the geometrical optics (GO) or ray optical solution. This UTD solution is shown to be very accurate by a numerical comparison with an exact reference solution.

A new UTD for the electromagnetic plane wave scattering by a canonical circular cylinder with an impedance boundary condition

A UTD solution is developed for describing the scattering by a circular cylinder with an impedance boundary condition (IBC), when it is illuminated by an obliquely incident electromagnetic (EM) plane wave. The solution to this canonical problem will be crucial for the construction of a more general UTD solution valid for an arbitrary smooth convex surface with an IBC, when it is illuminated by an arbitrary EM ray optical field. The canonical solution is uniformly valid across the surface shadow boundary that is tangent to the surface at grazing incidence. This canonical solution contains cross polarized terms in the scattered fields, which arise from a coupling of the TEz and TMz waves at the impedance boundary on the cylinder. Here, z is the cylinder axis. Numerical results show very good accuracy for the simpler and efficient UTD solution, when compared to exact but very slowly convergent eigenfunction solution.

Surface impedance for scattered field on a dielectric-coated circular cylinder

In the scattering analysis of a circular cylindrical structure, the impedance boundary condition (IBC) can approximate and simplify the perfect electric conductor (PEC) boundary condition. The circular cylinder problem can be solved with modal methods but they require a large number of terms when the cylinder radius is large in terms of the wave length. The uniform theory of diffraction (UTD) [1] is commonly used to overcome this issue. The two-dimensional problem of scattering on a circular cylinder covered by a dielectric layer has been analyzed by [2]–[5], but their solutions either do not consider oblique incidence, fail on the transition region or use a constant surface impedance.

Calcium-independent activation of endothelial nitric oxide synthase by ceramide

The endothelial isoform of NO synthase (eNOS) is targeted to sphingolipid-enriched signal-transducing microdomains in the plasma membrane termed caveolae. Among the caveolae-targeted sphingolipids are the ceramides, a class of acylated sphingosine compounds that have been implicated in diverse cellular responses. We have explored the role of ceramide analogues in eNOS signaling in cultured bovine aortic endothelial cells (BAEC). Addition of the ceramide analogue N-acetylsphingosine (C2-ceramide; 5 μM) to intact BAEC leads to a significant increase in NO synthase activity (assayed by using the fluorescent indicator 4,5-diaminofluorescein) and translocation of eNOS from the endothelial cell membrane to intracellular sites (measured by using quantitative immunofluorescence techniques); the biologically inactive ceramide N-acetyldihydrosphingosine is entirely without effect. C2-ceramide-induced eNOS activation and translocation are unaffected by the intracellular calcium chelator 1,2-bis-o-aminophenoxyethane-N,N,N′,N′-tetraacetic acid (BAPTA). Using the calcium-specific fluorescent indicator fluo-3, we also found that C2-ceramide activation of eNOS is unaccompanied by a drug-induced increase in intracellular calcium. These findings stand in sharp contrast to the mechanism by which bradykinin, estradiol, and other mediators acutely activate eNOS, in which a rapid, agonist-promoted increase in intracellular calcium is required. Finally, we show that treatment of BAEC with bradykinin causes a significant increase in cellular ceramide content; the response to bradykinin has an EC50 of 3 nM and is blocked by the bradykinin B2-receptor antagonist HOE140. Bradykinin-induced ceramide generation could represent a mechanism for longer-term regulation of eNOS activity. Our results suggest that ceramide functions independently of Ca2+-regulated pathways to promote activation and translocation of eNOS, and that this lipid mediator may represent a physiological regulator of eNOS in vascular endothelial cells.

The Werner Syndrome Protein Is Involved in RNA Polymerase II Transcription

Werner syndrome (WS) is a human progeroid syndrome characterized by the early onset of a large number of clinical features associated with the normal aging process. The complex molecular and cellular phenotypes of WS involve characteristic features of genomic instability and accelerated replicative senescence. The gene involved (WRN) was recently cloned, and its gene product (WRNp) was biochemically characterized as a helicase. Helicases play important roles in a variety of DNA transactions, including DNA replication, transcription, repair, and recombination. We have assessed the role of the WRN gene in transcription by analyzing the efficiency of basal transcription in WS lymphoblastoid cell lines that carry homozygous WRN mutations. Transcription was measured in permeabilized cells by [3H]UTP incorporation and in vitro by using a plasmid template containing the RNA polymerase II (RNA pol II)–dependent adenovirus major late promoter. With both of these approaches, we find that the transcription efficiency in different WS cell lines is reduced to 40–60% of the transcription in cells from normal individuals. This defect can be complemented by the addition of normal cell extracts to the chromatin of WS cells. Addition of purified wild-type WRNp but not mutated WRNp to the in vitro transcription assay markedly stimulates RNA pol II–dependent transcription carried out by nuclear extracts. A nonhelicase domain (a direct repeat of 27 amino acids) also appears to have a role in transcription enhancement, as revealed by a yeast hybrid–protein reporter assay. This is further supported by the lack of stimulation of transcription when mutant WRNp lacking this domain was added to the in vitro assay. We have thus used several approaches to show a role for WRNp in RNA pol II transcription, possibly as a transcriptional activator. A deficit in either global or regional transcription in WS cells may be a primary molecular defect responsible for the WS clinical phenotype.