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

Abstract

BackgroundMalaria 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.ResultsThe 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.ConclusionThis 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.

<i>In Silico</i> Evaluation of Anti-Malarial Agents from <i>Hoslundia opposita</i> as Inhibitors of <i>Plasmodium falciparum</i> Lactate Dehydrogenase (P<i>f</i>LDH) Enzyme

“…In the year 2013, the World Health Organization (WHO) estimated 198 million cases of malaria leading to 584,000 deaths worldwide [1]. The disease mostly prevails in the poor countries of tropical and sub-tropical regions of Sub-Saharan Africa, America and Asia [2]- [7]. The Plamodium species namely P. falciparum, P. vivax, P. malariae and P. ovale, and the lately reported species P. knowlesi are known to cause malaria [4] [5] [8] [9].…”

“…The Plamodium species namely P. falciparum, P. vivax, P. malariae and P. ovale, and the lately reported species P. knowlesi are known to cause malaria [4] [5] [8] [9]. Of the five species P. falciparum is the most responsible for causing the disease [2] [3] [5] [7].…”

Prediction of deleterious single nucleotide polymorphisms and their effect on the sequence and structure of the human CCND1 gene

“…The G1/S-specific cyclin-D1 protein sequence was downloaded from the UniProt database (P24385). 28 ProtParam 29 analysis showed that the protein has 295 amino acids. Its molecular weight is 33729.1 Da and its theoretical PI is 4.97.…”

Comparative molecular investigation of the potential inhibitors against SARS-CoV-2 main protease: a molecular docking study

“…This might be the result of several hydrogen bonding that was found such as Phe140, Glu166, Gln189, Asn142, and Pro168 at the active cavity of the main protease enzyme. Researcher suggests that non-covalent binding at the active site of the target protein may lead to possible inhibition and blockage of the protein (Hasan et al., 2015 ). On the other hand, the somatostatin analog, Vapreotide (VAP) was used to control tumor growth, progression, and metastasis.…”