title: De novo lead optimization of triazine derivatives identifies potent antimalarials.
abstract: Malaria is a life-threatening disease caused by Plasmodium parasites among which Plasmodium falciparum is the most deadly. Due to the widespread resistance of the current antimalarial drugs, intense research efforts are focused on identification of new and potent antimalarials. We report here, a structure based drug discovery strategy for design of a series of effective and novel triazine based antimalarials. The X-ray structure of P. falciparum methyl transferase (PfPMT) is used as a target as it is unique to the parasite. The triazine molecules designed and synthesized showed low micro-molar activity against malarial parasite cell lines. Molecular dynamics simulations on the PfPMT-inhibitor complex shed light on the inhibition mechanism for further optimization of the lead compounds.
authors.affiliation: Department of Chemistry and Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Delhi Hauz Khas, New Delhi, 110016, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shandilya
authors.affiliation: Jamia Millia Islamia, New Delhi, India.
authors.forename: Nasimul
authors.initials: N
authors.lastname: Hoda
authors.affiliation: Translational Health Science and Technology Institute, Gurgaon, India.
authors.forename: Sameena
authors.initials: S
authors.lastname: Khan
authors.affiliation: B.R. Ambedkar Bihar University, Muzaffarpur, India.
authors.forename: Ehtesham
authors.initials: E
authors.lastname: Jameel
authors.affiliation: Jamia Millia Islamia, New Delhi, India.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Kumar
authors.affiliation: Department of Chemistry and Supercomputing Facility for Bioinformatics & Computational Biology, Indian Institute of Technology, Delhi Hauz Khas, New Delhi, 110016, India; Kusuma School of Biological Sciences, IIT Delhi, New Delhi, India. Electronic address: bjayaram@chemistry.iitd.ac.in.
authors.forename: B
authors.initials: B
authors.lastname: Jayaram
mesh_terms: D000962:Antimalarials / Q000737:chemistry; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D014227:Triazines / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D014227:Triazines
keywords: Malaria; Molecular dynamics simulations; PfPMT; Triazine derivatives