Abstract

BackgroundPlasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite this, features contributing to such have not been exploited for anti-malarial drug design. Additionally, there are no anti-malarial drugs targeting PTKTs whereas the broad activity of these inhibitors against PTKTs from other Plasmodium spp. is yet to be reported. This study characterises different PTKTs [Plasmodium falciparum (PfTKT), Plasmodium vivax (PvTKT), Plasmodium ovale (PoTKT), Plasmodium malariae (PmTKT) and Plasmodium knowlesi (PkTKT) and the human homolog (HsTKT)] to identify key sequence and structural based differences as well as the identification of selective potential inhibitors against PTKTs.MethodsA sequence-based study was carried out using multiple sequence alignment, phylogenetic tree calculations and motif discovery analysis. Additionally, TKT models of PfTKT, PmTKT, PoTKT, PmTKT and PkTKT were modelled using the Saccharomyces cerevisiae TKT structure as template. Based on the modelled structures, molecular docking using 623 South African natural compounds was done. The stability, conformational changes and detailed interactions of selected compounds were accessed viz all-atom molecular dynamics (MD) simulations and binding free energy (BFE) calculations.ResultsSequence alignment, evolutionary and motif analyses revealed key differences between plasmodial and the human TKTs. High quality homodimeric three-dimensional PTKTs structures were constructed. Molecular docking results identified three compounds (SANC00107, SANC00411 and SANC00620) which selectively bind in the active site of all PTKTs with the lowest (better) binding affinity ≤ − 8.5 kcal/mol. MD simulations of ligand-bound systems showed stable fluctuations upon ligand binding. In all systems, ligands bind stably throughout the simulation and form crucial interactions with key active site residues. Simulations of selected compounds in complex with human TKT showed that ligands exited their binding sites at different time steps. BFE of protein–ligand complexes showed key residues involved in binding.ConclusionsThis study highlights significant differences between plasmodial and human TKTs and may provide valuable information for the development of novel anti-malarial inhibitors. Identified compounds may provide a starting point in the rational design of PTKT inhibitors and analogues based on these scaffolds.

Highlights

  • Plasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme

  • Transketolase (TKT), a key enzyme essential for parasite survival, is one of the novel pharmacological targets being explored as potential anti-malarial drug target [2]

  • Additional TKT sequences from Leishmania, Trypanosoma, bacteria, fungi and Anopheles (Plasmodium parasite vector) were retrieved from National Center for Biotechnology Information (NCBI) database [23] (Additional file 1)

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Summary

Introduction

Plasmodial transketolase (PTKT) enzyme is one of the novel pharmacological targets being explored as potential anti-malarial drug target due to its functional role and low sequence identity to the human enzyme. Despite the numerous anti-malarial drugs developed so far, the recurrent ability of the Plasmodium parasites to develop resistance against all existing chemotherapies remains the greatest challenge towards global malaria eradication [1]. Transketolase (TKT), a key enzyme essential for parasite survival, is one of the novel pharmacological targets being explored as potential anti-malarial drug target [2]. The C-terminal domain is made of 150 residues forming 5 stranded β-sheets This region is distant from the functional sites and is believed to be involved in the regulation of enzymatic activity as well as the stereochemical control of substrate binding [8]. Crystallized structures from Homo sapiens (HsTKT), Saccharomyces cerevisiae (ScTKT) and other organisms [11] already exist

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