title: A structural comparative approach to identifying novel antimalarial inhibitors.
abstract: Malaria continues to affect millions of people annually. With the rise of drug resistant strains, the need for alternative treatments has become increasingly urgent. Recently, PfUCHL3 was identified as an essential deubiquitinating enzyme. The increasing number of drug target structures being solved has increased the feasibility of utilizing a structural comparative approach to identifying novel inhibitors. Using AutoDock Vina, we recently screened the NCI library of about 320,000 compounds against the crystal structure of PfUCHL3. The top hits were subsequently screened against its human ortholog UCHL3 as to identify compounds that could specifically target the PfUCHL3 over its human counterpart. This method was used to identify small molecule inhibitors that can preferentially inhibit the parasitic enzyme. Several compounds were identified that demonstrated significant binding affinity preference for the malaria target over the human enzyme. Two of these compounds demonstrated ng/mL activity.
authors.affiliation: Department of Chemistry, Merrimack College, 315 Turnpike Street North Andover, MA 01845, United States. jfranco37@gmail.com
authors.forename: Jimmy
authors.initials: J
authors.lastname: Franco
authors.forename: Margaret A L
authors.initials: MA
authors.lastname: Blackie
authors.forename: David
authors.initials: D
authors.lastname: Toth
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.forename: Joseph
authors.initials: J
authors.lastname: Capuano
authors.forename: Kurt
authors.initials: K
authors.lastname: Fastnacht
authors.forename: Charlotte
authors.initials: C
authors.lastname: Berkes
mesh_terms: D000962:Antimalarials / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology*; D019295:Computational Biology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000201:enzymology*; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D043222:Ubiquitin Thiolesterase