Nilanjan Roy - Academia.edu (original) (raw)

Papers by Nilanjan Roy

Research paper thumbnail of LeishBase: Leishmania major structural database

Int. J. Integ. Biol, 2009

Three-dimensional (3D) protein structures are of great importance for the rational design and str... more Three-dimensional (3D) protein structures are of great importance for the rational design and structure-based discovery of specific inhibitors. Homology models of proteins play a significant role when no experimental three dimensional structures are available. LeishBase is a ...

Research paper thumbnail of Mrg19 depletion increases S. cerevisiae lifespan by augmenting ROS defence

FEBS letters, 2005

Caloric restriction (CR) is the most compelling example of lifespan extension by external manipul... more Caloric restriction (CR) is the most compelling example of lifespan extension by external manipulation. Although the molecular mechanisms remain unknown, the theory of hormesis has been invoked to explain the life promoting effects of CR. Hormesis is defined as the beneficial effects of low intensity stressor on a cell or organism. Mrg19 is a putative transcription factor that regulates carbon and nitrogen metabolism in yeast. In this study, we have found that deletion of MRG19 gene causes metabolic shift in yeast cells, leading to higher intracellular reactive oxygen species, augmentation of scavenging enzymes and longer lifespan compared to wild-type cells. All these results together suggest that similar to CR, depletion of Mrg19 leads to a condition of mild stress which in turn enhances vitality.

Research paper thumbnail of Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan

Nature Genetics, 2003

An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the... more An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the metabolism of many organisms shifts to growth or reproduction at the expense of longer lifespan, whereas a scarcity of nutrients reverses this shift 1-3. These correlations suggest that organisms respond to environmental changes by altering their metabolism to promote either reproduction and growth or long life. The only previously reported signaling mechanism involved in this response is the nutrient-responsive insulin/insulin-like growth factor-1 receptor pathway 1. Here we report another pathway that controls the length of yeast lifespan. Commitment to cell growth activates the Slt2p MAP kinase pathway, which phosphorylates the transcriptional silencing protein Sir3p, resulting in a shorter lifespan. Elimination of the Sir3p phosphorylation site at Ser275 extended lifespan by 38%. Lifespan extension occurs by a mechanism that is independent of suppressing rDNA recombination. Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan. Silencing in yeast is a chromatin-based phenomenon mediated by four Sir proteins that silence transcription at the silent-mating-type cassettes (HMRa and HMLα), the telomeres and the array of ribosomal RNA genes (the rDNA; refs. 4,5). Each locus has a unique set of DNA-binding proteins that recruit some or all of the Sir proteins. The size of the Sir protein pool limits the extent of silencing: telomere silencing is limited by the amount of available Sir3p 6 whereas rDNA silencing is limited by the availability of Sir2p 7. Telomeres are thought to be a reservoir for silencing proteins that can be redistributed to the silent-mating-type cassettes 8 and rDNA 7 .

Research paper thumbnail of Antibacterial sideroxylonals and loxophlebal A from Eucalyptus loxophleba foliage

Fitoterapia, 2010

Loxophlebal A, a new antibacterial formylated phloroglucinol was isolated from the mother liquor ... more Loxophlebal A, a new antibacterial formylated phloroglucinol was isolated from the mother liquor obtained after separation of sideroxylonals from the chloroform–methanol extract of leaves of Eucalyptus loxophleba ssp lissophloia. The structure of loxophlebal A was determined to ...

Research paper thumbnail of The mcm17 mutation of yeast shows a size-dependent segregational defect of a mini-chromosome

Current genetics, 1997

Mini-chromosome-maintenance (mcm) mu-tants were described earlier as yeast mutants which could no... more Mini-chromosome-maintenance (mcm) mu-tants were described earlier as yeast mutants which could not stably maintain mini-chromosomes. Out of these, the ARS-specific class has been more extensively studied and is found to lose chromosomes and ...

Research paper thumbnail of Synthesis and antibacterial activity evaluation of metronidazole–triazole conjugates

Bioorganic & Medicinal Chemistry Letters, 2009

Synthesis and antibacterial activity of metronidazole-triazole conjugates are reported. Total 21 ... more Synthesis and antibacterial activity of metronidazole-triazole conjugates are reported. Total 21 hybrid compounds have been synthesized with different substitution pattern on the triazole ring in order to study their influence on the antibacterial activity. These compounds demonstrated potent to weak antibacterial activity against Gram-positive, and Gram-negative bacteria. Six compounds have shown equal or better antibacterial activity against Gram-negative strains than the reference compound.

Research paper thumbnail of Escherichia coli versus Pseudomonas aeruginosa deacetylase LpxC inhibitors selectivity: surface and cavity-depth-based analysis

Research paper thumbnail of Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan

Nature Genetics, 2003

An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the... more An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the metabolism of many organisms shifts to growth or reproduction at the expense of longer lifespan, whereas a scarcity of nutrients reverses this shift 1-3. These correlations suggest that organisms respond to environmental changes by altering their metabolism to promote either reproduction and growth or long life. The only previously reported signaling mechanism involved in this response is the nutrient-responsive insulin/insulin-like growth factor-1 receptor pathway 1. Here we report another pathway that controls the length of yeast lifespan. Commitment to cell growth activates the Slt2p MAP kinase pathway, which phosphorylates the transcriptional silencing protein Sir3p, resulting in a shorter lifespan. Elimination of the Sir3p phosphorylation site at Ser275 extended lifespan by 38%. Lifespan extension occurs by a mechanism that is independent of suppressing rDNA recombination. Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan. Silencing in yeast is a chromatin-based phenomenon mediated by four Sir proteins that silence transcription at the silent-mating-type cassettes (HMRa and HMLα), the telomeres and the array of ribosomal RNA genes (the rDNA; refs. 4,5). Each locus has a unique set of DNA-binding proteins that recruit some or all of the Sir proteins. The size of the Sir protein pool limits the extent of silencing: telomere silencing is limited by the amount of available Sir3p 6 whereas rDNA silencing is limited by the availability of Sir2p 7. Telomeres are thought to be a reservoir for silencing proteins that can be redistributed to the silent-mating-type cassettes 8 and rDNA 7 .

Research paper thumbnail of Synthesis, antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives

Research paper thumbnail of Ring Modified Imidazoles as Novel Antifungal Compounds Targeted Against Fungal Histidinol Dehydrogenase

Research paper thumbnail of Probing the binding site of curcumin in Escherichia coli and Bacillus subtilis FtsZ – A structural insight to unveil antibacterial activity of curcumin

European Journal of Medicinal Chemistry, Sep 1, 2010

The cytoskeletal protein, FtsZ plays a pivotal role in prokaryotic cell division and is present i... more The cytoskeletal protein, FtsZ plays a pivotal role in prokaryotic cell division and is present in majority of the bacterial species. In recent years, inhibitors of FtsZ have been identified that may function as lead compounds for the development of novel antimicrobials. It has been found that curcumin, the main bioactive component of Curcuma longa, inhibits Bacillus subtilis and Escherichia coli growth by inhibiting FtsZ assembly. Though it is experimentally established that curcumin inhibits FtsZ polymerization, the binding site of curcumin in FtsZ is not known. In this study, interaction of curcumin with catalytic core domain of E. coli and B. subtilis FtsZ was investigated using computational docking.

Research paper thumbnail of Pharmacophoric features of Pseudomonas aeruginosa deacetylase LpxC inhibitors: An electronic and structural analysis

Bioorganic Medicinal Chemistry Letters, Feb 15, 2007

Various electronic properties of structurally diverse synthetic LpxC inhibitors containing oxazol... more Various electronic properties of structurally diverse synthetic LpxC inhibitors containing oxazoline, aroylserine and thiazoline rings were calculated and correlated with biological activity. These electronic features include the magnitude and locations of 3-dimensional molecular electrostatic potentials, hydrogen bond acceptor/donor density, lowest unoccupied molecular orbital, and highest occupied molecular orbital. Strong correlation of these stereo-electronic properties with LpxC inhibitory potency reveals the potential pharmacophoric features of specific LpxC inhibitors. Thus, these pharmacophoric features of LpxC inhibitors based on electronic and surface analysis could be successfully exploited for designing more potent LpxC inhibitors.

Research paper thumbnail of Identification of novel HIV-1 integrase inhibitors using shape-based screening and QSAR approach

ABSTRACT The objective of this study is to identify novel HIV-1 integrase (IN) inhibitors. Here, ... more ABSTRACT The objective of this study is to identify novel HIV-1 integrase (IN) inhibitors. Here, shape-based screening and QSAR have been successfully implemented to identify the novel inhibitors for HIV-1 IN, and in silico validation is performed by docking studies. The 2D QSAR model of benzodithiazine derivatives was built using genetic function approximation (GFA) method with good internal (cross-validated r(2) = 0.852) and external prediction (). Best docking pose of highly active molecule of the benzodithiazine derivatives was used as a template for shape-based screening of ZINC database. Toxicity prediction was also performed using Deductive Estimation of Risk from Existing Knowledge (DEREK) program to filter non-toxic molecules. Inhibitory activities of screened non-toxic molecules were predicted using derived QSAR models. Active, non-toxic screened molecules were also docked into the active site of HIV-1 IN using AutoDock and dock program. Some molecules docked similarly as highly active molecule of the benzodithiazine derivatives. These molecules also followed the same docking interactions in both the programs. Finally, four benzodithiazine derivatives were identified as novel HIV-1 integrase inhibitors based on QSAR predictions and docking interactions. ADME properties of these molecules were also computed using Discovery Studio.

Research paper thumbnail of Anti-leishmanial activity of the bisnaphthalimidopropyl derivatives

Parasitology international, 2012

Bisnaphthalimidopropyl (BNIP) derivatives were recently identified as inhibitors of the Leishmani... more Bisnaphthalimidopropyl (BNIP) derivatives were recently identified as inhibitors of the Leishmania Silent Information Regulator 2 (SIR2) NAD(+)-dependent deacetylase. In this report we have for the first time, determined the potential of these compounds to treat visceral leishmaniasis using BALB/c mice chronically infected with Leishmania infantum as a model. These experiments led to the identification of BNIPdiaminooctane (BNIPDaoct) as an effective compound able to induce significant reduction of the parasite load in the spleen and in the liver. Indeed, at a dose of 1mg/kg, BNIPDaoct was more effective to treat leishmaniasis in a short course treatment (3 or 6 drug administrations) than the standard amphotericin B. Moreover, no indications of hematological toxicity were detected as evaluated by the hemoglobin, hematocrit, white and red blood cell counts, hence making BNIPDaoct a potential therapeutic agent against leishmaniasis.

Research paper thumbnail of Evaluation of Proinflammatory Cytokine Pathway Inhibitors for p38 MAPK Inhibitory Potential

Journal of Medicinal Chemistry, 2007

The target for the anti-inflammatory natural products like amentoflavone ( 2), which act by inter... more The target for the anti-inflammatory natural products like amentoflavone ( 2), which act by interfering with the proinflammatory cytokine pathway (e.g., TNF-alpha, IL-1beta, and NO synthase), is not yet well-defined. Data obtained from docking, electronic, and surface analyses shed some light on steric and electronic complementarity of these molecules to p38 MAPK, thereby suggesting a possible mechanism by which they might reduce the production of proinflammatory cytokines.

Research paper thumbnail of Sustained release nanoparticulate formulation containing antioxidant-ellagic acid as potential prophylaxis system for oral administration

Journal of Drug Targeting, 2006

The aim of the present work was to develop ellagic acid (EA) loaded poly(D,L-lactide-co-glycolide... more The aim of the present work was to develop ellagic acid (EA) loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles for oral administration. PLGA nanoparticles were prepared by a method based on the concept of emulsion-diffusionevaporation by using polyethylene glycol (PEG) 400 as a cosolvent for solubilizing the drug. While developing this method, didodecyldimethylammomium bromide (DMAB) and polyvinyl alcohol (PVA), alone and in combination with chitosan (CS) were employed. DMAB stabilized particles were the smallest of all the formulations with a particle size of 148.5 nm. PVA alone gave particles of 269.7 nm but a blend with CS (80:20) resulted in an increase in particle size (359.6^23.6 nm). Initial release of EA from nanoparticles in pH 7.4 phosphate buffer was rapid, followed by a slower sustained release. Release rates followed the order PVA. PVA-CS. DMAB. Release rate from the PLGA-DMAB particles was slowest, which is attributed to higher hydrophobicity of DMAB as compared to PVA, preventing diffusion of drug out of polymeric matrix. Insolubility of CS at alkaline pH could have retarded the release in case of PVA-CS system. In situ intestinal permeability study of pure drug and the drug encapsulated in nanoparticles prepared using PVA, PVA-CS blend and DMAB as stabilizer in rats showed 66, 75, 73 and 87% permeation, respectively. EA showed good free radical scavenging effect in a yeast cell culture model as well as in a cell free system.

Research paper thumbnail of Evaluation of Pseudomonas aeruginosa Deacetylase LpxC Inhibitory Activity of Dual PDE4−TNFα Inhibitors:  A Multiscreening Approach

Journal of Chemical Information and Modeling, 2007

In this study, we have focused on the implication of a multiscreening approach in the evaluation ... more In this study, we have focused on the implication of a multiscreening approach in the evaluation of Pseudomonas aeruginosa deacetylase LpxC inhibitory activity of dual PDE4-TNFalpha inhibitors. A genetic function approximation (GFA) directed quantitative structure-activity relationship (QSAR) model was developed for LpxC inhibition on the basis of reported biological activity (Kline and Andersen, J. Med. Chem. 2002, 45, 3112-3129). Subsequently, reported PDE4-TNFalpha inhibitors (Klienman and Campbell, J. Med. Chem. 1998, 41, 266-270) were screened using the QSAR model. Whereby, the compounds were predicted to have equipotent activity with the most potent compound in reported LpxC inhibitor series. A docking analysis of these compounds carried out on the LpxC homology model corroborated the initial results. The compounds were then validated using surface electronic properties analysis and subjected to an adsorption, distribution, metabolism, excretion, and toxicity filter. Taken together, a multiscreening strategy was used to validate potential leads for LpxC inhibition.

Research paper thumbnail of Meta-analysis of glutathione S-transferase M1 genotype and risk toward head and neck cancer

Head & Neck, 2006

Background. We sought to evaluate the estimated risk of GSTM1 null genotype and squamous cell car... more Background. We sought to evaluate the estimated risk of GSTM1 null genotype and squamous cell carcinoma of the head and neck (SCCHN). Methods. The studies done so far for GSTM1 null genotype as a risk factor associated with head and neck cancer are not conclusive and have shown conflicting results. A meta-analysis has been carried out on 22 case-control studies collected from the literature. Precision of the risk estimate and presence of publication bias in those studies are also evaluated by funnel plot analysis. Results. A total of 3527 cases and 4211 controls constitute the subjects of meta-analysis. The principal outcome measured was the odds ratio (OR) for the risk of head and neck cancer. Pooling the studies together, the OR was 1.50 (95% confidence interval [CI], 1.21-1.87). When stratified according to Asians and Caucasians, the OR increased in the Asians (OR, 1.93; 95% CI, 1.29-2.90), suggesting that the risk is more pronounced in Asians. However, a substantial amount of publication bias is also associated with studies conducted on the Asian population. Conclusion. A review of the 22 case-control studies for risk of SCCHN and GSTM1 null genotype indicate that greater attention should be paid to designing future studies so that a more precise risk estimate can be achieved.

Research paper thumbnail of Nicotinamide inhibits Plasmodium falciparum Sir2 activity in vitro and parasite growth

FEMS Microbiology Letters, 2008

Plasmodium falciparum sirtuin, PfSir2, contains histone deacetylase (HDAC) activity that may be c... more Plasmodium falciparum sirtuin, PfSir2, contains histone deacetylase (HDAC) activity that may be central to the regulation of virulence gene expression in the parasites. Although a few reports have been published recently regarding in vitro and in vivo function of PfSir2, expression of the endogenous protein (c. 30 kDa) has not been shown yet. Here we report the presence of PfSir2 in the parasite at the protein level by specific antibodies. HDAC activity of PfSir2 can be inhibited by nicotinamide, a product of sirtuin reaction. Surprisingly, we find that nicotinamide also delays parasite growth significantly in culture. These findings further our knowledge on PfSir2 and raise the possibility of using an inexpensive agent like nicotinamide as an antimalarial in combination with other antiparasitic drugs.

Research paper thumbnail of The ZDS1 and ZDS2 proteins require the Sir3p component of yeast silent chromatin to enhance the stability of short linear centromeric plasmids

Chromosoma, 1999

Yeast artificial chromosome (YAC) clones of Saccharomyces cerevisiae containing a centromere, ori... more Yeast artificial chromosome (YAC) clones of Saccharomyces cerevisiae containing a centromere, origin of replication, two telomeres and a >50 kb insert of DNA are maintained as normal yeast chromosomes. However, short linear centromeric plasmids of 10-15 kb in size (short YACs) are missegregated at a much higher frequency than long YACs or 10-15 kb circular centromeric plasmids. A search for genes that stabilized short linear centromeric plasmids when present in multiple copies per cell uncovered ZDS1, which reduced the rate at which cells lost the short YAC, increased the fraction of cells that maintained the short YAC and decreased the number of short YACs per cell. Multiple copies of ZDS2, a homolog of ZDS1, had similar effects. Genes near yeast telomeres are transcriptionally silenced by the recruitment of proteins encoded by the SIR2, SIR3 and SIR4 genes (Sir2p, Sir3p and Sir4p). Multiple copies of ZDS1 and ZDS2 caused an increase in telomeric silencing. In addition, ZDS1 and ZDS2 both required the open reading frame encoding the N-terminal 174 amino acids of Sir3p to stabilize short YACs. Thus, the short YAC stability assay revealed a silencing-independent function for the Sir3p N-terminus. Two-hybrid analysis indicated that Zds1p and Zds2p interact with Sir2p, Sir3p, Sir4p or the yeast telomere binding protein Rap1p. Deletion of both ZDS1 and ZDS2 made short YACs, but not a 100 kb YAC, extremely unstable and also caused a 70 bp increase in the length of the telomeric TG1-3 repeats. These data indicate that short YACs can be stabilized by trans-acting factors and suggest that the proteins encoded by ZDS1 and ZDS2 alter short YAC stability by interacting with proteins that function at the telomere.

Research paper thumbnail of LeishBase: Leishmania major structural database

Int. J. Integ. Biol, 2009

Three-dimensional (3D) protein structures are of great importance for the rational design and str... more Three-dimensional (3D) protein structures are of great importance for the rational design and structure-based discovery of specific inhibitors. Homology models of proteins play a significant role when no experimental three dimensional structures are available. LeishBase is a ...

Research paper thumbnail of Mrg19 depletion increases S. cerevisiae lifespan by augmenting ROS defence

FEBS letters, 2005

Caloric restriction (CR) is the most compelling example of lifespan extension by external manipul... more Caloric restriction (CR) is the most compelling example of lifespan extension by external manipulation. Although the molecular mechanisms remain unknown, the theory of hormesis has been invoked to explain the life promoting effects of CR. Hormesis is defined as the beneficial effects of low intensity stressor on a cell or organism. Mrg19 is a putative transcription factor that regulates carbon and nitrogen metabolism in yeast. In this study, we have found that deletion of MRG19 gene causes metabolic shift in yeast cells, leading to higher intracellular reactive oxygen species, augmentation of scavenging enzymes and longer lifespan compared to wild-type cells. All these results together suggest that similar to CR, depletion of Mrg19 leads to a condition of mild stress which in turn enhances vitality.

Research paper thumbnail of Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan

Nature Genetics, 2003

An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the... more An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the metabolism of many organisms shifts to growth or reproduction at the expense of longer lifespan, whereas a scarcity of nutrients reverses this shift 1-3. These correlations suggest that organisms respond to environmental changes by altering their metabolism to promote either reproduction and growth or long life. The only previously reported signaling mechanism involved in this response is the nutrient-responsive insulin/insulin-like growth factor-1 receptor pathway 1. Here we report another pathway that controls the length of yeast lifespan. Commitment to cell growth activates the Slt2p MAP kinase pathway, which phosphorylates the transcriptional silencing protein Sir3p, resulting in a shorter lifespan. Elimination of the Sir3p phosphorylation site at Ser275 extended lifespan by 38%. Lifespan extension occurs by a mechanism that is independent of suppressing rDNA recombination. Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan. Silencing in yeast is a chromatin-based phenomenon mediated by four Sir proteins that silence transcription at the silent-mating-type cassettes (HMRa and HMLα), the telomeres and the array of ribosomal RNA genes (the rDNA; refs. 4,5). Each locus has a unique set of DNA-binding proteins that recruit some or all of the Sir proteins. The size of the Sir protein pool limits the extent of silencing: telomere silencing is limited by the amount of available Sir3p 6 whereas rDNA silencing is limited by the availability of Sir2p 7. Telomeres are thought to be a reservoir for silencing proteins that can be redistributed to the silent-mating-type cassettes 8 and rDNA 7 .

Research paper thumbnail of Antibacterial sideroxylonals and loxophlebal A from Eucalyptus loxophleba foliage

Fitoterapia, 2010

Loxophlebal A, a new antibacterial formylated phloroglucinol was isolated from the mother liquor ... more Loxophlebal A, a new antibacterial formylated phloroglucinol was isolated from the mother liquor obtained after separation of sideroxylonals from the chloroform–methanol extract of leaves of Eucalyptus loxophleba ssp lissophloia. The structure of loxophlebal A was determined to ...

Research paper thumbnail of The mcm17 mutation of yeast shows a size-dependent segregational defect of a mini-chromosome

Current genetics, 1997

Mini-chromosome-maintenance (mcm) mu-tants were described earlier as yeast mutants which could no... more Mini-chromosome-maintenance (mcm) mu-tants were described earlier as yeast mutants which could not stably maintain mini-chromosomes. Out of these, the ARS-specific class has been more extensively studied and is found to lose chromosomes and ...

Research paper thumbnail of Synthesis and antibacterial activity evaluation of metronidazole–triazole conjugates

Bioorganic & Medicinal Chemistry Letters, 2009

Synthesis and antibacterial activity of metronidazole-triazole conjugates are reported. Total 21 ... more Synthesis and antibacterial activity of metronidazole-triazole conjugates are reported. Total 21 hybrid compounds have been synthesized with different substitution pattern on the triazole ring in order to study their influence on the antibacterial activity. These compounds demonstrated potent to weak antibacterial activity against Gram-positive, and Gram-negative bacteria. Six compounds have shown equal or better antibacterial activity against Gram-negative strains than the reference compound.

Research paper thumbnail of Escherichia coli versus Pseudomonas aeruginosa deacetylase LpxC inhibitors selectivity: surface and cavity-depth-based analysis

Research paper thumbnail of Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan

Nature Genetics, 2003

An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the... more An organism's lifespan is modulated by environmental conditions. When nutrients are abundant, the metabolism of many organisms shifts to growth or reproduction at the expense of longer lifespan, whereas a scarcity of nutrients reverses this shift 1-3. These correlations suggest that organisms respond to environmental changes by altering their metabolism to promote either reproduction and growth or long life. The only previously reported signaling mechanism involved in this response is the nutrient-responsive insulin/insulin-like growth factor-1 receptor pathway 1. Here we report another pathway that controls the length of yeast lifespan. Commitment to cell growth activates the Slt2p MAP kinase pathway, which phosphorylates the transcriptional silencing protein Sir3p, resulting in a shorter lifespan. Elimination of the Sir3p phosphorylation site at Ser275 extended lifespan by 38%. Lifespan extension occurs by a mechanism that is independent of suppressing rDNA recombination. Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan. Silencing in yeast is a chromatin-based phenomenon mediated by four Sir proteins that silence transcription at the silent-mating-type cassettes (HMRa and HMLα), the telomeres and the array of ribosomal RNA genes (the rDNA; refs. 4,5). Each locus has a unique set of DNA-binding proteins that recruit some or all of the Sir proteins. The size of the Sir protein pool limits the extent of silencing: telomere silencing is limited by the amount of available Sir3p 6 whereas rDNA silencing is limited by the availability of Sir2p 7. Telomeres are thought to be a reservoir for silencing proteins that can be redistributed to the silent-mating-type cassettes 8 and rDNA 7 .

Research paper thumbnail of Synthesis, antimicrobial, and antioxidant activity of benzofuran barbitone and benzofuran thiobarbitone derivatives

Research paper thumbnail of Ring Modified Imidazoles as Novel Antifungal Compounds Targeted Against Fungal Histidinol Dehydrogenase

Research paper thumbnail of Probing the binding site of curcumin in Escherichia coli and Bacillus subtilis FtsZ – A structural insight to unveil antibacterial activity of curcumin

European Journal of Medicinal Chemistry, Sep 1, 2010

The cytoskeletal protein, FtsZ plays a pivotal role in prokaryotic cell division and is present i... more The cytoskeletal protein, FtsZ plays a pivotal role in prokaryotic cell division and is present in majority of the bacterial species. In recent years, inhibitors of FtsZ have been identified that may function as lead compounds for the development of novel antimicrobials. It has been found that curcumin, the main bioactive component of Curcuma longa, inhibits Bacillus subtilis and Escherichia coli growth by inhibiting FtsZ assembly. Though it is experimentally established that curcumin inhibits FtsZ polymerization, the binding site of curcumin in FtsZ is not known. In this study, interaction of curcumin with catalytic core domain of E. coli and B. subtilis FtsZ was investigated using computational docking.

Research paper thumbnail of Pharmacophoric features of Pseudomonas aeruginosa deacetylase LpxC inhibitors: An electronic and structural analysis

Bioorganic Medicinal Chemistry Letters, Feb 15, 2007

Various electronic properties of structurally diverse synthetic LpxC inhibitors containing oxazol... more Various electronic properties of structurally diverse synthetic LpxC inhibitors containing oxazoline, aroylserine and thiazoline rings were calculated and correlated with biological activity. These electronic features include the magnitude and locations of 3-dimensional molecular electrostatic potentials, hydrogen bond acceptor/donor density, lowest unoccupied molecular orbital, and highest occupied molecular orbital. Strong correlation of these stereo-electronic properties with LpxC inhibitory potency reveals the potential pharmacophoric features of specific LpxC inhibitors. Thus, these pharmacophoric features of LpxC inhibitors based on electronic and surface analysis could be successfully exploited for designing more potent LpxC inhibitors.

Research paper thumbnail of Identification of novel HIV-1 integrase inhibitors using shape-based screening and QSAR approach

ABSTRACT The objective of this study is to identify novel HIV-1 integrase (IN) inhibitors. Here, ... more ABSTRACT The objective of this study is to identify novel HIV-1 integrase (IN) inhibitors. Here, shape-based screening and QSAR have been successfully implemented to identify the novel inhibitors for HIV-1 IN, and in silico validation is performed by docking studies. The 2D QSAR model of benzodithiazine derivatives was built using genetic function approximation (GFA) method with good internal (cross-validated r(2) = 0.852) and external prediction (). Best docking pose of highly active molecule of the benzodithiazine derivatives was used as a template for shape-based screening of ZINC database. Toxicity prediction was also performed using Deductive Estimation of Risk from Existing Knowledge (DEREK) program to filter non-toxic molecules. Inhibitory activities of screened non-toxic molecules were predicted using derived QSAR models. Active, non-toxic screened molecules were also docked into the active site of HIV-1 IN using AutoDock and dock program. Some molecules docked similarly as highly active molecule of the benzodithiazine derivatives. These molecules also followed the same docking interactions in both the programs. Finally, four benzodithiazine derivatives were identified as novel HIV-1 integrase inhibitors based on QSAR predictions and docking interactions. ADME properties of these molecules were also computed using Discovery Studio.

Research paper thumbnail of Anti-leishmanial activity of the bisnaphthalimidopropyl derivatives

Parasitology international, 2012

Bisnaphthalimidopropyl (BNIP) derivatives were recently identified as inhibitors of the Leishmani... more Bisnaphthalimidopropyl (BNIP) derivatives were recently identified as inhibitors of the Leishmania Silent Information Regulator 2 (SIR2) NAD(+)-dependent deacetylase. In this report we have for the first time, determined the potential of these compounds to treat visceral leishmaniasis using BALB/c mice chronically infected with Leishmania infantum as a model. These experiments led to the identification of BNIPdiaminooctane (BNIPDaoct) as an effective compound able to induce significant reduction of the parasite load in the spleen and in the liver. Indeed, at a dose of 1mg/kg, BNIPDaoct was more effective to treat leishmaniasis in a short course treatment (3 or 6 drug administrations) than the standard amphotericin B. Moreover, no indications of hematological toxicity were detected as evaluated by the hemoglobin, hematocrit, white and red blood cell counts, hence making BNIPDaoct a potential therapeutic agent against leishmaniasis.

Research paper thumbnail of Evaluation of Proinflammatory Cytokine Pathway Inhibitors for p38 MAPK Inhibitory Potential

Journal of Medicinal Chemistry, 2007

The target for the anti-inflammatory natural products like amentoflavone ( 2), which act by inter... more The target for the anti-inflammatory natural products like amentoflavone ( 2), which act by interfering with the proinflammatory cytokine pathway (e.g., TNF-alpha, IL-1beta, and NO synthase), is not yet well-defined. Data obtained from docking, electronic, and surface analyses shed some light on steric and electronic complementarity of these molecules to p38 MAPK, thereby suggesting a possible mechanism by which they might reduce the production of proinflammatory cytokines.

Research paper thumbnail of Sustained release nanoparticulate formulation containing antioxidant-ellagic acid as potential prophylaxis system for oral administration

Journal of Drug Targeting, 2006

The aim of the present work was to develop ellagic acid (EA) loaded poly(D,L-lactide-co-glycolide... more The aim of the present work was to develop ellagic acid (EA) loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles for oral administration. PLGA nanoparticles were prepared by a method based on the concept of emulsion-diffusionevaporation by using polyethylene glycol (PEG) 400 as a cosolvent for solubilizing the drug. While developing this method, didodecyldimethylammomium bromide (DMAB) and polyvinyl alcohol (PVA), alone and in combination with chitosan (CS) were employed. DMAB stabilized particles were the smallest of all the formulations with a particle size of 148.5 nm. PVA alone gave particles of 269.7 nm but a blend with CS (80:20) resulted in an increase in particle size (359.6^23.6 nm). Initial release of EA from nanoparticles in pH 7.4 phosphate buffer was rapid, followed by a slower sustained release. Release rates followed the order PVA. PVA-CS. DMAB. Release rate from the PLGA-DMAB particles was slowest, which is attributed to higher hydrophobicity of DMAB as compared to PVA, preventing diffusion of drug out of polymeric matrix. Insolubility of CS at alkaline pH could have retarded the release in case of PVA-CS system. In situ intestinal permeability study of pure drug and the drug encapsulated in nanoparticles prepared using PVA, PVA-CS blend and DMAB as stabilizer in rats showed 66, 75, 73 and 87% permeation, respectively. EA showed good free radical scavenging effect in a yeast cell culture model as well as in a cell free system.

Research paper thumbnail of Evaluation of Pseudomonas aeruginosa Deacetylase LpxC Inhibitory Activity of Dual PDE4−TNFα Inhibitors:  A Multiscreening Approach

Journal of Chemical Information and Modeling, 2007

In this study, we have focused on the implication of a multiscreening approach in the evaluation ... more In this study, we have focused on the implication of a multiscreening approach in the evaluation of Pseudomonas aeruginosa deacetylase LpxC inhibitory activity of dual PDE4-TNFalpha inhibitors. A genetic function approximation (GFA) directed quantitative structure-activity relationship (QSAR) model was developed for LpxC inhibition on the basis of reported biological activity (Kline and Andersen, J. Med. Chem. 2002, 45, 3112-3129). Subsequently, reported PDE4-TNFalpha inhibitors (Klienman and Campbell, J. Med. Chem. 1998, 41, 266-270) were screened using the QSAR model. Whereby, the compounds were predicted to have equipotent activity with the most potent compound in reported LpxC inhibitor series. A docking analysis of these compounds carried out on the LpxC homology model corroborated the initial results. The compounds were then validated using surface electronic properties analysis and subjected to an adsorption, distribution, metabolism, excretion, and toxicity filter. Taken together, a multiscreening strategy was used to validate potential leads for LpxC inhibition.

Research paper thumbnail of Meta-analysis of glutathione S-transferase M1 genotype and risk toward head and neck cancer

Head & Neck, 2006

Background. We sought to evaluate the estimated risk of GSTM1 null genotype and squamous cell car... more Background. We sought to evaluate the estimated risk of GSTM1 null genotype and squamous cell carcinoma of the head and neck (SCCHN). Methods. The studies done so far for GSTM1 null genotype as a risk factor associated with head and neck cancer are not conclusive and have shown conflicting results. A meta-analysis has been carried out on 22 case-control studies collected from the literature. Precision of the risk estimate and presence of publication bias in those studies are also evaluated by funnel plot analysis. Results. A total of 3527 cases and 4211 controls constitute the subjects of meta-analysis. The principal outcome measured was the odds ratio (OR) for the risk of head and neck cancer. Pooling the studies together, the OR was 1.50 (95% confidence interval [CI], 1.21-1.87). When stratified according to Asians and Caucasians, the OR increased in the Asians (OR, 1.93; 95% CI, 1.29-2.90), suggesting that the risk is more pronounced in Asians. However, a substantial amount of publication bias is also associated with studies conducted on the Asian population. Conclusion. A review of the 22 case-control studies for risk of SCCHN and GSTM1 null genotype indicate that greater attention should be paid to designing future studies so that a more precise risk estimate can be achieved.

Research paper thumbnail of Nicotinamide inhibits Plasmodium falciparum Sir2 activity in vitro and parasite growth

FEMS Microbiology Letters, 2008

Plasmodium falciparum sirtuin, PfSir2, contains histone deacetylase (HDAC) activity that may be c... more Plasmodium falciparum sirtuin, PfSir2, contains histone deacetylase (HDAC) activity that may be central to the regulation of virulence gene expression in the parasites. Although a few reports have been published recently regarding in vitro and in vivo function of PfSir2, expression of the endogenous protein (c. 30 kDa) has not been shown yet. Here we report the presence of PfSir2 in the parasite at the protein level by specific antibodies. HDAC activity of PfSir2 can be inhibited by nicotinamide, a product of sirtuin reaction. Surprisingly, we find that nicotinamide also delays parasite growth significantly in culture. These findings further our knowledge on PfSir2 and raise the possibility of using an inexpensive agent like nicotinamide as an antimalarial in combination with other antiparasitic drugs.

Research paper thumbnail of The ZDS1 and ZDS2 proteins require the Sir3p component of yeast silent chromatin to enhance the stability of short linear centromeric plasmids

Chromosoma, 1999

Yeast artificial chromosome (YAC) clones of Saccharomyces cerevisiae containing a centromere, ori... more Yeast artificial chromosome (YAC) clones of Saccharomyces cerevisiae containing a centromere, origin of replication, two telomeres and a >50 kb insert of DNA are maintained as normal yeast chromosomes. However, short linear centromeric plasmids of 10-15 kb in size (short YACs) are missegregated at a much higher frequency than long YACs or 10-15 kb circular centromeric plasmids. A search for genes that stabilized short linear centromeric plasmids when present in multiple copies per cell uncovered ZDS1, which reduced the rate at which cells lost the short YAC, increased the fraction of cells that maintained the short YAC and decreased the number of short YACs per cell. Multiple copies of ZDS2, a homolog of ZDS1, had similar effects. Genes near yeast telomeres are transcriptionally silenced by the recruitment of proteins encoded by the SIR2, SIR3 and SIR4 genes (Sir2p, Sir3p and Sir4p). Multiple copies of ZDS1 and ZDS2 caused an increase in telomeric silencing. In addition, ZDS1 and ZDS2 both required the open reading frame encoding the N-terminal 174 amino acids of Sir3p to stabilize short YACs. Thus, the short YAC stability assay revealed a silencing-independent function for the Sir3p N-terminus. Two-hybrid analysis indicated that Zds1p and Zds2p interact with Sir2p, Sir3p, Sir4p or the yeast telomere binding protein Rap1p. Deletion of both ZDS1 and ZDS2 made short YACs, but not a 100 kb YAC, extremely unstable and also caused a 70 bp increase in the length of the telomeric TG1-3 repeats. These data indicate that short YACs can be stabilized by trans-acting factors and suggest that the proteins encoded by ZDS1 and ZDS2 alter short YAC stability by interacting with proteins that function at the telomere.