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  • We conclude that Tetrapleura tetraptera fruits

    2024-05-30

    We conclude that Tetrapleura tetraptera fruits extract possess antiplasmodial activity and the results of this study justifies and confirms the traditional usage of this plant as malarial remedy.
    Acknowledgement
    Introduction The phylum apicomplexa comprises of nearly 5000 species, most of which are parasites and are the causative agents of various pernicious diseases [1]. The most prominent apicomplexa is the Plasmodium species, which is the causative agent of malaria, a disease that is affecting nearly 300–500 million people every year worldwide. With the resurrection of drug resistant Plasmodium falciparum, the most fatal human malaria parasite, identification of new possible medicinal targets is an extreme priority. In such scenario, P. falciparum genome has facilitated the description of several metabolic pathways, particularly those differing from humans; thus providing new targets for drug development [2], [3]. The shikimate pathway, in apicomplexan parasites provides a promising and exciting opportunity for reaching such objectives, as the pathway is only found in algae, plants, bacteria, protozoa and fungi, but is absent from mammals. The pathway is responsible for the formation of key aromatic Bupivacaine HCl involved in primary metabolism. In addition, the pathway in apicomplexa is important for the supply of folates, for which animals rely exclusively on an exogenous source [4]. Moreover, some of the enzymes of the pathway catalyze biochemically unique reactions in nature, making them excellent targets for new antiparasite drugs. Enzymes of this metabolic pathway have been studied extensively by various authors [5], [6], [7]. Chorismate synthase (EC 4.2.3.5) is the last enzyme of the pathway which catalyzes the conversion of the 5-enolpyruvylshikimate-3-phosphate (EPSP) to chorismate. The CS reaction comprises an anti-1,4-elimination of the 3-phosphate group and the C-6 pro R hydrogen with requirement of reduced FMN as a cofactor [8], [9]. The catalysis action of CS does not involve any overall change in redox state, hence it is considered to be unique reaction in nature [9]. According to Bornemann et al., the reduced FMN donates an electron to EPSP to facilitate the loss of the phosphate and receive it back after the reaction [8]. According to the functionality, CS has been divided into two classes, monofunctional and bifunctional. Chorismate synthases from plants and eubacteria possess only trans elimination activity of substrate and are called monofunctional. However, CS from Neurospora crassa and Saccharomyces cerevisiae have an additional NADPH:FMN oxidoreductase activity, so-called bifunctional. Despite of resemblance with fungal CS, PfCS is reported to be monofunctional [10]. In the present study, we performed in silico molecular modeling of three-dimensional structure of chorismate synthase enzyme from P. falciparum. We also performed an in silico structure-based inhibitors study using various substrate analogs and in vitro characterized inhibitors series. In absence of the crystal structure, we hope that the proposed 3D model will be helpful for providing novel target for structure based drug design against malaria.
    Methodology The computational analysis was done on Intel Core i3-2.13GHz Processor running on Windows 2007 Home Basic. The AUTODOCK version 4 and Molecular Dynamics (MD) simulations (GROMACS) were performed on Red Hat Enterprise Linux 5 operation system (Red Hat Inc., Raleigh, NC) installed on a Dell Precision T5400 workstation [11], [12]. The Molecular Docking was performed on GLIDE 5.5 program (Glide, version 5.5, Schrödinger, LLC, New York, NY, 2009) running on Windows 2003 on a HP xw8400 Workstation. All the graphical analysis and image production was done using PyMOL [13] and WinCoot software [14].
    Result and discussion
    CS is one of the few untouched targets for developing anti-malaria drugs. Generation of a reliable model has opened the possibilities of computer-assisted inhibitor design against PfCS. To achieve Ideogram objective within a reasonable time scale, we have used GLIDE docking software version 5.5 [33]. During the study of putative inhibitors using GLIDE, the protein–ligand interacting site was restricted to the binding site of the EPSP (as discussed in Section 3.6). To screen the ligand(s) that bound to the active site of PfCS, we used EPSP analogs available in PubChem database as well as the previously reported inhibitors of Streptococcus pneumoniae CS (SpCS) [34].