scholarly journals Investigation on Nuclear Transport of Trypanosoma brucei: An in silico Approach

10.5772/48108 ◽  
2012 ◽  
Author(s):  
Mohd Fakharul Zaman Raja Yahya ◽  
Umi Marshida Abdul Hamid ◽  
Farida Zuraina Mohd Yusof
Keyword(s):  
Trypanosoma Brucei ◽  
In Silico ◽  
Nuclear Transport

scholarly journals Genetic and structural study of DNA-directed RNA polymerase II of Trypanosoma brucei, towards the designing of novel antiparasitic agents

2017 ◽  
Author(s):  
Louis Papageorgiou ◽  
Vasileios Megalooikonomou ◽  
Dimitrios Vlachakis
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Trypanosoma Brucei ◽  
In Silico ◽  
State Of The Art ◽  
Pharmacophore Model ◽  
Tsetse Flies ◽  
Structural Level ◽  
Enzyme Model ◽  
Pharmacological Interest

Trypanosoma brucei brucei (TBB) belongs to the unicellular parasitic protozoa organisms, specifically to the Trypanosoma genus of the Trypanosomatidae class. A variety of different vertebrate species can be infected by TBB including humans and animals. Under particular conditions, the TBB can be hosted by wild and domestic animals; thereby an important reservoir of infection always remains available to transmit through the tsetse flies. Although the TBB parasite is one of the leading causes of death in the most underdeveloped countries, to date, there is neither vaccination available nor any drug against TBB infection. The subunit RPB1 of the TBB DNA-directed RNA polymerase II (DdRpII) constitutes an ideal target for the design of novel inhibitors, since it is instrumental role is vital for the parasite’s survival, proliferation, and transmission. A major goal of the described study is to provide insights for novel anti-TBB agents via a state of the art drug discovery approach of the TBB DdRpII RPB1. In an attempt to understand the function and action mechanisms of this parasite enzyme related to its molecular structure, an in-depth evolutionary study has been conducted in parallel to the in silico molecular designing of the 3D enzyme model, based on state of the art comparative modelling and molecular dynamics techniques. Based on theevolutionary studies results nine new invariant, first-time reported, highly conserved regions have been identified within the DdRpII family enzymes. Consequently, those patches have been examined both at the sequence and structural level and have been evaluated in regards to their pharmacological targeting appropriateness. Finally, the pharmacophore elucidation study enabled us to virtually in silico screenhundreds of compounds and evaluate their interaction capabilities with the enzyme. It was found that a series of Chlorine-rich set of compounds were the optimal inhibitors for the TBB DdRpII RPB1 enzyme. All-in-all, herein we present a series of new sites on the TBB DdRpII RPB1 of high pharmacological interest, alongside the construction of the 3D model of the enzyme and the suggestion of a new in silico pharmacophore model for fast screening of potential inhibiting agents.

scholarly journals Genome-wide in silico screen for CCCH-type zinc finger proteins of Trypanosoma brucei, Trypanosoma cruzi and Leishmania major

BMC Genomics ◽  
2010 ◽  
Vol 11 (1) ◽  
pp. 283 ◽  
Author(s):  
Susanne Kramer ◽  
Nicola C Kimblin ◽  
Mark Carrington
Keyword(s):  
Trypanosoma Cruzi ◽  
Trypanosoma Brucei ◽  
Zinc Finger ◽  
In Silico ◽  
Leishmania Major ◽  
Zinc Finger Proteins ◽  
Genome Wide

scholarly journals In Silico Identification and in Vitro Activity of Novel Natural Inhibitors of Trypanosoma brucei Glyceraldehyde-3-phosphate-dehydrogenase

Molecules ◽  
2015 ◽  
Vol 20 (9) ◽  
pp. 16154-16169 ◽  
Author(s):  
Fabian Herrmann ◽  
Mairin Lenz ◽  
Joachim Jose ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
In Silico ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
In Silico Identification ◽  
Natural Inhibitors

scholarly journals Compartmentation prevents a lethal turbo-explosion of glycolysis in trypanosomes

2008 ◽  
Vol 105 (46) ◽  
pp. 17718-17723 ◽  
Author(s):  
Jurgen R. Haanstra ◽  
Arjen van Tuijl ◽  
Peter Kessler ◽  
Willem Reijnders ◽  
Paul A. M. Michels ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
In Silico ◽  
Protein Import ◽  
Feedback Inhibition ◽  
Allosteric Regulation ◽  
Feedback Regulation ◽  
Glucose Addition ◽  
Experimental Support ◽  
Atp Generation

ATP generation by both glycolysis and glycerol catabolism is autocatalytic, because the first kinases of these pathways are fuelled by ATP produced downstream. Previous modeling studies predicted that either feedback inhibition or compartmentation of glycolysis can protect cells from accumulation of intermediates. The deadly parasite Trypanosoma brucei lacks feedback regulation of early steps in glycolysis yet sequesters the relevant enzymes within organelles called glycosomes, leading to the proposal that compartmentation prevents toxic accumulation of intermediates. Here, we show that glucose 6-phosphate indeed accumulates upon glucose addition to PEX14 deficient trypanosomes, which are impaired in glycosomal protein import. With glycerol catabolism, both in silico and in vivo, loss of glycosomal compartmentation led to dramatic increases of glycerol 3-phosphate upon addition of glycerol. As predicted by the model, depletion of glycerol kinase rescued PEX14-deficient cells of glycerol toxicity. This provides the first experimental support for our hypothesis that pathway compartmentation is an alternative to allosteric regulation.

scholarly journals Genetic and structural study of DNA-directed RNA polymerase II of Trypanosoma brucei, towards the designing of novel antiparasitic agents

2017 ◽  
Author(s):  
Louis Papageorgiou ◽  
Vasileios Megalooikonomou ◽  
Dimitrios Vlachakis
Keyword(s):  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Trypanosoma Brucei ◽  
In Silico ◽  
State Of The Art ◽  
Pharmacophore Model ◽  
Tsetse Flies ◽  
Structural Level ◽  
Enzyme Model ◽  
Pharmacological Interest

Trypanosoma brucei brucei (TBB) belongs to the unicellular parasitic protozoa organisms, specifically to the Trypanosoma genus of the Trypanosomatidae class. A variety of different vertebrate species can be infected by TBB including humans and animals. Under particular conditions, the TBB can be hosted by wild and domestic animals; thereby an important reservoir of infection always remains available to transmit through the tsetse flies. Although the TBB parasite is one of the leading causes of death in the most underdeveloped countries, to date, there is neither vaccination available nor any drug against TBB infection. The subunit RPB1 of the TBB DNA-directed RNA polymerase II (DdRpII) constitutes an ideal target for the design of novel inhibitors, since it is instrumental role is vital for the parasite’s survival, proliferation, and transmission. A major goal of the described study is to provide insights for novel anti-TBB agents via a state of the art drug discovery approach of the TBB DdRpII RPB1. In an attempt to understand the function and action mechanisms of this parasite enzyme related to its molecular structure, an in-depth evolutionary study has been conducted in parallel to the in silico molecular designing of the 3D enzyme model, based on state of the art comparative modelling and molecular dynamics techniques. Based on theevolutionary studies results nine new invariant, first-time reported, highly conserved regions have been identified within the DdRpII family enzymes. Consequently, those patches have been examined both at the sequence and structural level and have been evaluated in regards to their pharmacological targeting appropriateness. Finally, the pharmacophore elucidation study enabled us to virtually in silico screenhundreds of compounds and evaluate their interaction capabilities with the enzyme. It was found that a series of Chlorine-rich set of compounds were the optimal inhibitors for the TBB DdRpII RPB1 enzyme. All-in-all, herein we present a series of new sites on the TBB DdRpII RPB1 of high pharmacological interest, alongside the construction of the 3D model of the enzyme and the suggestion of a new in silico pharmacophore model for fast screening of potential inhibiting agents.

scholarly journals Sesquiterpene Lactones with Dual Inhibitory Activity against the Trypanosoma brucei Pteridine Reductase 1 and Dihydrofolate Reductase

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 149
Author(s):  
Katharina Possart ◽  
Fabian Herrmann ◽  
Joachim Jose ◽  
Maria Costi ◽  
Thomas Schmidt
Keyword(s):  
Trypanosoma Brucei ◽  
Dihydrofolate Reductase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Gene Knockout ◽  
Sesquiterpene Lactones ◽  
Treatment Options ◽  
Cattle Disease ◽  
Ic50 Values

The parasite Trypanosoma brucei (T. brucei) is responsible for human African trypanosomiasis (HAT) and the cattle disease “Nagana” which to this day cause severe medical and socio-economic issues for the affected areas in Africa. So far, most of the available treatment options are accompanied by harmful side effects and are constantly challenged by newly emerging drug resistances. Since trypanosomatids are auxotrophic for folate, their pteridine metabolism provides a promising target for an innovative chemotherapeutic treatment. They are equipped with a unique corresponding enzyme system consisting of the bifunctional dihydrofolate reductase-thymidylate synthase (TbDHFR-TS) and the pteridine reductase 1 (TbPTR1). Previously, gene knockout experiments with PTR1 null mutants have underlined the importance of these enzymes for parasite survival. In a search for new chemical entities with a dual inhibitory activity against the TbPTR1 and TbDHFR, a multi-step in silico procedure was employed to pre-select promising candidates against the targeted enzymes from a natural product database. Among others, the sesquiterpene lactones (STLs) cynaropicrin and cnicin were identified as in silico hits. Consequently, an in-house database of 118 STLs was submitted to an in silico screening yielding 29 further virtual hits. Ten STLs were subsequently tested against the target enzymes in vitro in a spectrophotometric inhibition assay. Five compounds displayed an inhibition over 50% against TbPTR1 as well as three compounds against TbDHFR. Cynaropicrin turned out to be the most interesting hit since it inhibited both TbPTR1 and TbDHFR, reaching IC50 values of 12.4 µM and 7.1 µM, respectively.

scholarly journals Megazol and its bioisostere 4H-1,2,4-triazole: comparing the trypanocidal, cytotoxic and genotoxic activities and their in vitro and in silico interactions with the Trypanosoma brucei nitroreductase enzyme

2014 ◽  
Vol 109 (3) ◽  
pp. 315-323 ◽  
Author(s):  
Alcione Silva de Carvalho ◽  
Kelly Salomão ◽  
Solange Lisboa de Castro ◽  
Taline Ramos Conde ◽  
Helena Pereira da Silva Zamith ◽  
...  
Keyword(s):  
Trypanosoma Brucei ◽  
In Silico
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