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Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment.

Hasan MA, Mazumder MH, Chowdhury AS, Datta A, Khan MA - Source Code Biol Med (2015)

Bottom Line: As a result, demands for new targets for more effective anti-malarial drugs are escalating.This predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity.However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331 Bangladesh.

ABSTRACT

Background: Malaria has been a major life threatening mosquito borne disease from long since. Unavailability of any effective vaccine and recent emergence of multi drug resistant strains of malaria pathogen Plasmodium falciparum continues to cause persistent deaths in the tropical and sub-tropical region. As a result, demands for new targets for more effective anti-malarial drugs are escalating. Transketolase is an enzyme of the pentose phosphate pathway; a novel pathway which is involved in energy generation and nucleic acid synthesis. Moreover, significant difference in homology between Plasmodium falciparum transketolase (Pftk) and human (Homo sapiens) transketolase makes it a suitable candidate for drug therapy. Our present study is aimed to predict the 3D structure of Plasmodium falciparum transketolase and design an inhibitor against it.

Results: The primary and secondary structural features of the protein is calculated by ProtParam and SOPMA respectively which revealed the protein is composed of 43.3 % alpha helix and 33.04 % random coils along with 15.62 % extended strands, 8.04 % beta turns. The three dimensional structure of the transketolase is constructed using homology modeling tool MODELLAR utilizing several available transketolase structures as templates. The structure is then subjected to deep optimization and validated by structure validation tools PROCHECK, VERIFY 3D, ERRAT, QMEAN. The predicted model scored 0.74 for global model reliability in PROCHECK analysis, which ensures the quality of the model. According to VERIFY 3D the predicted model scored 0.77 which determines good environmental profile along with ERRAT score of 78.313 which is below 95 % rejection limit. Protein-protein and residue-residue interaction networks are generated by STRING and RING server respectively. CASTp server was used to analyze active sites and His 109, Asn 108 and His 515 are found to be more positive site to dock the substrate, in addition molecular docking simulation with Autodock vina determined the estimated free energy of molecular binding was of -6.6 kcal/mol for most favorable binding of 6'-Methyl-Thiamin Diphosphate.

Conclusion: This predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity. However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.

No MeSH data available.


Related in: MedlinePlus

The overall binding between the transketolase and 6′-Methyl-Thiamin Diphosphate. a Biological assembly of transketolase and 6′-Methyl-Thiamin Diphosphate, b Mesh structure of transketolase and 6′-Methyl-Thiamin Diphosphate, c Surface structure of transketolase and 6′-Methyl-Thiamin Diphosphate, d Cartoon structure of transketolase and 6′-Methyl-Thiamin Diphosphate
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Fig11: The overall binding between the transketolase and 6′-Methyl-Thiamin Diphosphate. a Biological assembly of transketolase and 6′-Methyl-Thiamin Diphosphate, b Mesh structure of transketolase and 6′-Methyl-Thiamin Diphosphate, c Surface structure of transketolase and 6′-Methyl-Thiamin Diphosphate, d Cartoon structure of transketolase and 6′-Methyl-Thiamin Diphosphate

Mentions: The complete profile of the studies by AutoDock Vina, is represented in Table 5. For the most favorable binding 6′-Methyl-Thiamin Diphosphate, estimated free energy of molecular binding was of −6.6 kcal/mol. The overall binding energies as well as RMSD (Å) of 6′-Methyl-Thiamin Diphosphate based on their rank are tabulated in Table 4. Overall binding of transketolase and 6′-Methyl-Thiamin Diphosphate is represented in Fig. 11. It has been found that 6′-Methyl-Thiamin Diphosphate formed 5 Hydrogen bonds with the transketolase (Fig. 12). The Amino acid residues conscientious for the binding interactions of the 6′-Methyl-Thiamin Diphosphate (Fig. 11b) with the enzyme are His 109, His 515, Asn 108. The description of 6′-Methyl-Thiamin Diphosphate is given in Table 6. After analyzing the results, in case of our selected ligand it is clearly concluded that this has a crucial role in ligand binding affinity.Table 5


Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment.

Hasan MA, Mazumder MH, Chowdhury AS, Datta A, Khan MA - Source Code Biol Med (2015)

The overall binding between the transketolase and 6′-Methyl-Thiamin Diphosphate. a Biological assembly of transketolase and 6′-Methyl-Thiamin Diphosphate, b Mesh structure of transketolase and 6′-Methyl-Thiamin Diphosphate, c Surface structure of transketolase and 6′-Methyl-Thiamin Diphosphate, d Cartoon structure of transketolase and 6′-Methyl-Thiamin Diphosphate
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4472393&req=5

Fig11: The overall binding between the transketolase and 6′-Methyl-Thiamin Diphosphate. a Biological assembly of transketolase and 6′-Methyl-Thiamin Diphosphate, b Mesh structure of transketolase and 6′-Methyl-Thiamin Diphosphate, c Surface structure of transketolase and 6′-Methyl-Thiamin Diphosphate, d Cartoon structure of transketolase and 6′-Methyl-Thiamin Diphosphate
Mentions: The complete profile of the studies by AutoDock Vina, is represented in Table 5. For the most favorable binding 6′-Methyl-Thiamin Diphosphate, estimated free energy of molecular binding was of −6.6 kcal/mol. The overall binding energies as well as RMSD (Å) of 6′-Methyl-Thiamin Diphosphate based on their rank are tabulated in Table 4. Overall binding of transketolase and 6′-Methyl-Thiamin Diphosphate is represented in Fig. 11. It has been found that 6′-Methyl-Thiamin Diphosphate formed 5 Hydrogen bonds with the transketolase (Fig. 12). The Amino acid residues conscientious for the binding interactions of the 6′-Methyl-Thiamin Diphosphate (Fig. 11b) with the enzyme are His 109, His 515, Asn 108. The description of 6′-Methyl-Thiamin Diphosphate is given in Table 6. After analyzing the results, in case of our selected ligand it is clearly concluded that this has a crucial role in ligand binding affinity.Table 5

Bottom Line: As a result, demands for new targets for more effective anti-malarial drugs are escalating.This predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity.However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chittagong, 4331 Bangladesh.

ABSTRACT

Background: Malaria has been a major life threatening mosquito borne disease from long since. Unavailability of any effective vaccine and recent emergence of multi drug resistant strains of malaria pathogen Plasmodium falciparum continues to cause persistent deaths in the tropical and sub-tropical region. As a result, demands for new targets for more effective anti-malarial drugs are escalating. Transketolase is an enzyme of the pentose phosphate pathway; a novel pathway which is involved in energy generation and nucleic acid synthesis. Moreover, significant difference in homology between Plasmodium falciparum transketolase (Pftk) and human (Homo sapiens) transketolase makes it a suitable candidate for drug therapy. Our present study is aimed to predict the 3D structure of Plasmodium falciparum transketolase and design an inhibitor against it.

Results: The primary and secondary structural features of the protein is calculated by ProtParam and SOPMA respectively which revealed the protein is composed of 43.3 % alpha helix and 33.04 % random coils along with 15.62 % extended strands, 8.04 % beta turns. The three dimensional structure of the transketolase is constructed using homology modeling tool MODELLAR utilizing several available transketolase structures as templates. The structure is then subjected to deep optimization and validated by structure validation tools PROCHECK, VERIFY 3D, ERRAT, QMEAN. The predicted model scored 0.74 for global model reliability in PROCHECK analysis, which ensures the quality of the model. According to VERIFY 3D the predicted model scored 0.77 which determines good environmental profile along with ERRAT score of 78.313 which is below 95 % rejection limit. Protein-protein and residue-residue interaction networks are generated by STRING and RING server respectively. CASTp server was used to analyze active sites and His 109, Asn 108 and His 515 are found to be more positive site to dock the substrate, in addition molecular docking simulation with Autodock vina determined the estimated free energy of molecular binding was of -6.6 kcal/mol for most favorable binding of 6'-Methyl-Thiamin Diphosphate.

Conclusion: This predicted structure of Pftk will serve first hand in the future development of effective Pftk inhibitors with potential anti-malarial activity. However, this is a preliminary study of designing an inhibitor against Plasmodium falciparum 3D7; the results await justification by in vitro and in vivo experimentations.

No MeSH data available.


Related in: MedlinePlus