title: Screening and Identification of Inhibitors Against Glutathione Synthetase, A Potential Drug Target of Plasmodium falciparum.
abstract: Malaria is the world's most fatal disease - causing up to 2.7 million deaths annually all over the world. The ability of organisms to develop resistance against existing antimalarial drugs exacerbates the problem. There is a clear cut need for more effective, affordable and accessible drugs that act by novel modes of action. Glutathione synthetase (GS) from Plasmodium falciparum represents an important potential drug target due to its defensive role; hence ceasing the respective metabolic step will destroy the parasite. A three dimensional model of Plasmodium GS was constructed by de novo modelling method and potential GS inhibitors were identified from a library of glutathione (GSH) analogues retrieved from Ligand-info database and filtered using Lipinski and ADME rules. Two common feature pharmacophore models were generated from the individual inhibitor clusters to provide insight into the key pharmacophore features that are crucial for the GS inhibition. Molecular docking of selective compounds into the predicted GS binding site revealed that the compound CMBMB was the best GS inhibitor when compared to the standard reference Chloroquine (CQ). This was taken as indicating that CMBMB was the best effective and safest drug against P. falciparum.
authors.affiliation: Biomedical Informatics Centre, Vector Control Research Centre (ICMR), Indira Nagar, Pondicherry, 605006, India. nandakumaryellapu@gmail.com.
authors.forename: Yellapu Nanda
authors.initials: YN
authors.lastname: Kumar
authors.forename: Gopal
authors.initials: G
authors.lastname: Jeyakodi
authors.forename: Ramamoorthy
authors.initials: R
authors.lastname: Thulasibabu
authors.forename: Kasinathan
authors.initials: K
authors.lastname: Gunasekaran
authors.forename: Purushothaman
authors.initials: P
authors.lastname: Jambulingam
mesh_terms: D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000737:chemistry / Q000494:pharmacology*; D005981:Glutathione Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D005981:Glutathione Synthase; D005978:Glutathione