<i>In Silico</i>
            Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis

Kaur, Jaspreet; Kumar, Pranav; Tyagi, Sargam; Pathak, Richa; Batra, Sanjay; Singh, Prashant; Singh, Neeloo

doi:10.1128/aac.00436-10

Cited by 31 publications

(17 citation statements)

References 23 publications

(22 reference statements)

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“…In silico protein analysis has received great attention lately, with particular emphasis in finding suitable biomarkers for the diagnosis of infectious or noninfectious diseases, identification of different pathogenic genera (Kumar, Koul, Kumar, & Kalia, ), new drug development (Kaur et al, ) and for the discovery of potent bioactive peptides and proteins with potential biotechnological use (N. Singh & Kashyap, ). Phyre2 is one of the most widely used protein structure prediction servers, processing approximately 700–1,000 user‐submitted proteins per day (Kelley et al, ).…”

Section: Discussionmentioning

confidence: 99%

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

Weber

Alves

Abujamra

et al. 2018

Molecular Reproduction Devel

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Human secondary hypogonadism is associated with impaired testicular function, however, little is known about its impact on sperm epididymal maturation. Endocrine disruption in the epididymis could impair the secretion of key proteins, such as β‐defensins, responsible for spermatozoa maturation during epididymal transit. This study evaluated the sequence and structural similarities between porcine epididymal β‐defensins porcine β‐defensins (pBD3), pBD4, pBD125, and pEP2C and their human homologs using bioinformatics integrated with information derived from protein databanks. We then verified whether the expression of pBD3, pBD4, pBD125, and pEP2C genes in the testis and epididymis are influenced by disruption of the hypothalamic‐pituitary‐testicular (HPT) axis in a pig model for male human secondary hypogonadism. Upon modeling porcine β‐defensins, structural and functional analysis confirmed the presence of motifs associated with β‐defensin function, validating the models generated in silico. pBD3 and pBD4 showed acceptable structural alignments with human β‐defensins BDEF103 and BDEF110, respectively. In addition, evaluation of hormonal regulation of β‐defensins was assessed by analyzing the expression of these four β‐defensins in adult boars immunized against gonadotropin‐releasing hormone (GnRH). Our results indicate that HPT axis disruption modifies the expression of pBD3, pBD4, pBD125, and pEP2C in boar testis and epididymis, suggesting an endocrine‐dependent regulation of β‐defensins in swine epididymis. In conclusion, sequence and structural homology between pBD3 and pBD4 and their human homologs provide a basis for using the pig as a model for the study of human secondary hypogonadism. Further investigation of the human homologs in hypogonadal men could elucidate the connections between fertility and epididymal expression of β‐defensins.

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Section: Discussionmentioning

confidence: 99%

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

Weber

Alves

Abujamra

et al. 2018

Molecular Reproduction Devel

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“…The J774A.1 mouse (BALB/c) macrophage cell line was obtained from the National Centre for Cell Science (Pune, India) and used as a cellular host for the in vitro intracellular test of antileishmanial activity against amastigotes. The cells were maintained in RPMI 1640 medium (Gibco-BRL) adjusted to contain 2 g of sodium bicarbonate/ liter, 6 g of HEPES/liter, 10% (vol/vol) heat-inactivated fetal bovine serum (HI-FBS; Gibco, Germany), and 100 U penicillin and 100 g of streptomycin/ml at 37°C in a humidified atmosphere of 95% air and 5% CO 2 (26).…”

Section: Synthesis Of Ag Nps and Tiomentioning

confidence: 99%

Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G ₀ /G ₁ Arrest followed by Necrotic Cell Death in Leishmania donovani

Zahir¹,

Chauhan

Bagavan³

et al. 2015

Antimicrob Agents Chemother

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155

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The aim of the present study was to synthesize silver (Ag) and titanium dioxide (TiO 2 ) nanoparticles (NPs) using green synthesis from aqueous leaf extract of Euphorbia prostrata as antileishmanial agents and to explore the underlying molecular mechanism of induced cell death. In vitro antileishmanial activity of synthesized NPs was tested against promastigotes of Leishmania donovani by alamarBlue and propidium iodide uptake assays. Antileishmanial activity of synthesized NPs on intracellular amastigotes was assessed by Giemsa staining. The leishmanicidal effect of synthesized Ag NPs was further confirmed by DNA fragmentation assay and by cell cycle progression and transmission electron microscopy (TEM) of the treated parasites. TEM analysis of the synthesized Ag NPs showed a spherical shape with an average size of 12.82 ؎ 2.50 nm, and in comparison to synthesized TiO 2 NPs, synthesized Ag NPs were found to be most active against Leishmania parasites after 24 h exposure, with 50% inhibitory concentrations (IC 50 ) of 14.94 g/ml and 3.89 g/ml in promastigotes and intracellular amastigotes, respectively. A significant increase in G 0 /G 1 phase of the cell cycle with a subsequent decrease in S (synthesis) and G 2 /M phases compared to controls was observed. The growth-inhibitory effect of synthesized Ag NPs was attributed to increased length of S phase. A decreased reactive oxygen species level was also observed, which could be responsible for the caspase-independent shift from apoptosis (G 0 /G 1 arrest) to massive necrosis. High-molecular-weight DNA fragmentation as a positive consequence of necrotic cell death was also visualized. We also report that the unique trypanothione/trypanothione reductase (TR) system of Leishmania cells was significantly inhibited by synthesized Ag NPs. The green-synthesized Ag NPs may provide promising leads for the development of costeffective and safer alternative treatment against visceral leishmaniasis.

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“…The "in-silico" analysis which stands for computer-based biological experiments, is a state-of-the-art and accurate method to discover exclusive bioactive compounds, which may represent novel metabolic pathways and/or a powerful affinity to a certain target (42). In this sense, several studies have identified unprecedented molecules for various drug targets in Leishmania, such as pteridine reductase1, tryparedoxin peroxidase and sterol biosynthesis (43)(44)(45)(46)(47)(48), as well as in other single-celled eukaryotes enclosing Toxoplasma gondii, Cryptosporidium hominis, Plasmodium and Trypanosoma cruzi (49)(50)(51). Current in-silico investigation was aimed to screen and predict the anti-leishmanial potency of 3358 FDA-approved compounds against both drug targets in L. infantum in comparison to amphotericin B and glucantime for the discovery of new biochemical molecules.…”

Section: Discussionmentioning

confidence: 99%

In-Silico Identification of the Best Compound Against <i>Leishmania infantum</i>: High Throughput Screening of All FDA Approved Drugs

Saki

Shadnoush

Arjmand

et al. 2019

Turkiye Parazitol Derg

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Amaç: Mevcut in-silico araştırması, Leishmania infantum lipofosfoglikan (LPG) ve γ-glutamilsistein sentetazına (γ-GCS) karşı umut verici ilaçlar bulmak amacıyla 20000 Gıda ve İlaç İdaresi onaylı ilaç bileşiklerinin taranması için tasarlandı ve uygulandı. Yöntemler: Her iki hedefin protein sekansı alındıktan sonra, 3D yapıları tahmin edildi ve doğrulandı. Moleküler yerleştirme iki varsayılan hedef (LPG ve γ-GCS) arasında yapıldı ve ligand-reseptör etkileşimlerini tahmin etmek için AutoDock 4.2 programı kullanılarak onaylanmış bileşikler seçildi. Bulgular: Yirmi bin ilaç bileşiği üzerinde deney yapıldıktan sonra, γ-GCS reseptörü için iki ve LPG reseptörü için beş olmak üzere toplam yedi ligand, bağlanma afiniteleri ve enerjilerine göre yeni, güçlü anti-leishmanial ilaçlar olarak belirlenmiştir. Bunlardan 5 ligand 8,5 kcal/mol'e kadar daha negatif Δ Gbinding ile LPG reseptörüne iyi bağlanma kapasitesi gösteren sitotoksik ve anti-kanser özelliklere sahipti. Bunlardan 2 ligand, 7,8 kcal/mol'e kadar daha negatif Δ Gbinding ile glutamil reseptörüne iyi bir bağlanma kapasitesi gösterdi. Sonuç: En yeni yazılım tabanlı yöntemler, yeni ilaç keşfi için organizmalarda biyolojik hedeflere özgü yeni peptid şablonlarını taramak ve tahmin etmek için güçlü araçlardır. Bununla birlikte, in vitro ve in vivo tekniklerin kullanımı, öngörülen ligandların öz Objective: Current in-silico research was designed and administered for the screening of 20000 Food and Drug Administrationapproved drug compounds with the goal of finding promising drugs against lipophosphoglycan (LPG) and γ-glutamylcysteine synthetase (γ-GCS) of Leishmania infantum. Methods: After the protein sequence of both targets was taken, the 3D structures of protein of interest were predicted and validated. Molecular docking was done among the two putative targets (LPG and γ-GCS) and approved compounds were selected using AutoDock 4.2 program to predict ligand-receptor interactions. Results: After docking experiment was done on 20000 drug compounds, a total number of seven ligands, two for γ-GCS receptor and five for LPG receptor, were assigned as novel, potent anti-leishmanial drugs based on their binding affinity and energy. Of those, five ligands possessed cytotoxic and anti-cancer characteristics and showed good binding capacity to LPG receptor with Δ Gbinding up to 8.5 kcal/mol more negative; while two compounds showed good binding capacity to glutamyl receptor with Δ Gbinding up to 7.8 kcal/mol more negative. Conclusion: The latest software-based methods are powerful tools for scanning and predicting new peptide templates specific to biological targets in organisms for new drug discovery. However, the use of in vitro and in vivo techniques is a requirement for better evaluation of the potential of projected ligands with the help of in-silico approaches, identifying molecular mechanism of action of the more active compounds is possible. This can help in defining the most likely molecular target, so that the subsequent optimization using in vitro and in vivo techniques ...

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In Silico Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis

Cited by 31 publications

References 23 publications

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G ₀ /G ₁ Arrest followed by Necrotic Cell Death in Leishmania donovani

In-Silico Identification of the Best Compound Against <i>Leishmania infantum</i>: High Throughput Screening of All FDA Approved Drugs

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In Silico Screening, Structure-Activity Relationship, and Biologic Evaluation of Selective Pteridine Reductase Inhibitors Targeting Visceral Leishmaniasis

Cited by 31 publications

References 23 publications

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

Structural modeling and mRNA expression of epididymal β‐defensins in GnRH immunized boars: A model for secondary hypogonadism in man

Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G 0 /G 1 Arrest followed by Necrotic Cell Death in Leishmania donovani

In-Silico Identification of the Best Compound Against <i>Leishmania infantum</i>: High Throughput Screening of All FDA Approved Drugs

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Product

Resources

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Green Synthesis of Silver and Titanium Dioxide Nanoparticles Using Euphorbia prostrata Extract Shows Shift from Apoptosis to G ₀ /G ₁ Arrest followed by Necrotic Cell Death in Leishmania donovani