Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

Sheng, Chunquan; Ji, Haitao; Miao, Zhenyuan; Che, Xiaoyin; Yao, Jing; Wang, Wenya; Dong, Guoqiang; Guo, Wei; Lü, Jing; Zhang, Wannian

doi:10.1007/s10822-009-9267-2

Cited by 21 publications

(11 citation statements)

References 41 publications

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“…Structural modeling of the binding cavities in the T. brucei and L. major NMT proteins suggest that NMT analogs interact with the active site via hydrophobic, hydrogen bonding, and ionic interactions with both positively and negatively charged residues [84]. The major difference in T. brucei and L. major enzymes compared to other NMTS is the presence of additional positively charged residues in the binding cavity [84].…”

Section: Acylation As a Drug Targetmentioning

confidence: 99%

“…The major difference in T. brucei and L. major enzymes compared to other NMTS is the presence of additional positively charged residues in the binding cavity [84]. Although the L. donovani enzyme lacks the extra charged residues in the binding cavity, there is no structural overlap in this region between LdNMTs and either human or other protozoan NMTs, suggesting that any inhibitors of L. donovani NMTs will be selective [85].…”

Section: Acylation As a Drug Targetmentioning

confidence: 99%

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Acylation in trypanosomatids: an essential process and potential drug target

Goldston

Sharma

Paul

et al. 2014

Trends in Parasitology

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Fatty acylation—the addition of fatty acid moieties such as myristate and palmitate to proteins—is essential for the survival, growth, and infectivity of the trypanosomatids: Trypanosoma brucei, Trypanosoma cruzi, and Leishmania. Myristoylation and palmitoylation are critical for parasite growth, targeting and localization, and the intrinsic function of some proteins. The trypanosomatids possess a single N-myristoyltransferase (NMT) and multiple palmitoyl acyltransferases, and these enzymes and their cellular targets are only now being characterized. Global inhibition of either process leads to cell death in trypanosomatids, and genetic ablation of NMT compromises virulence. Moreover, NMT inhibitors effectively cure T. brucei infection in rodents. Thus, protein acylation represents an attractive target for the development of trypanocidal drugs.

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Section: Acylation As a Drug Targetmentioning

confidence: 99%

Section: Acylation As a Drug Targetmentioning

confidence: 99%

Acylation in trypanosomatids: an essential process and potential drug target

Goldston

Sharma

Paul

et al. 2014

Trends in Parasitology

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“…Several inhibitors of fungal NMTs (Figure 9) inhibit the trypanosomal enzyme, and growth of T. brucei in vitro [106, 107]. Though these molecules are not drug-like, they have been employed for homology modeling using crystallographic information from fungal NMTs to suggest opportunities for rational design of new T. brucei selective inhibitors [108]. …”

Section: Fatty Acid Utilizationmentioning

confidence: 99%

State of the Art in African Trypanosome Drug Discovery

Jacobs

Nare

Phillips

2011

CTMC

116

139

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African sleeping sickness is endemic in sub-Saharan Africa where the WHO estimates that 60 million people are at risk for the disease. Human African trypanosomiasis (HAT) is 100% fatal if untreated and the current drug therapies have significant limitations due to toxicity and difficult treatment regimes. No new chemical agents have been approved since eflornithine in 1990. The pentamidine analog DB289, which was in late stage clinical trials for the treatment of early stage HAT recently failed due to toxicity issues. A new protocol for the treatment of late-stage T. brucei gambiense that uses combination nifurtomox/eflornithine (NECT) was recently shown to have better safety and efficacy than eflornithine alone, while being easier to administer. This breakthrough represents the only new therapy for HAT since the approval of eflornithine. A number of research programs are on going to exploit the unusual biochemical pathways in the parasite to identify new targets for target based drug discovery programs. HTS efforts are also underway to discover new chemical entities through whole organism screening approaches. A number of inhibitors with anti-trypanosomal activity have been identified by both approaches, but none of the programs are yet at the stage of identifying a preclinical candidate. This dire situation underscores the need for continued effort to identify new chemical agents for the treatment of HAT.

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“…The time steps of one femtosecond were applied to all simulations. All of these simulations were done at neutral pH (Asp, Glu, Arg and Lys ionized) ( 45 , 46 ).…”

Section: Methodsmentioning

confidence: 99%

Comparison of Newly Assembled Full Length HIV-1 Integrase With Prototype Foamy Virus Integrase: Structure-Function Prospective

Dayer

2016

Jundishapur J Microbiol

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BackgroundDrug design against human immunodeficiency virus type 1 (HIV-1) integrase through its mechanistic study is of great interest in the area in biological research. The main obstacle in this area is the absence of the full-length crystal structure for HIV-1 integrase to be used as a model. A complete structure, similar to HIV-1 of a prototype foamy virus integrase in complex with DNA, including all conservative residues, is available and has been extensively used in recent investigations.ObjectivesThe aim of this study was to determine whether the above model is precisely representative of HIV-1 integrase. This would critically determine the success of any designed drug using the model in deactivation of integrase and AIDS treatment.Materials and MethodsPrimarily, a new structure for HIV-1 was constructed, using a crystal structure of prototype foamy virus as the starting structure. The constructed structure of HIV-1 integrase was simultaneously simulated with a prototype foamy virus integrase on a separate occasion.ResultsOur results indicate that the HIV-1 system behaves differently from the prototype foamy virus in terms of folding, hydration, hydrophobicity of binding site and stability.ConclusionsBased on our findings, we can conclude that HIV-1 integrase is vastly different from the prototype foamy virus integrase and does not resemble it, and the modeling output of the prototype foamy virus simulations could not be simply generalized to HIV-1 integrase. Therefore, our HIV-1 model seems to be more representative and more useful for future research.

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Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design

Cited by 21 publications

References 41 publications

Acylation in trypanosomatids: an essential process and potential drug target

Acylation in trypanosomatids: an essential process and potential drug target

State of the Art in African Trypanosome Drug Discovery

Comparison of Newly Assembled Full Length HIV-1 Integrase With Prototype Foamy Virus Integrase: Structure-Function Prospective

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