title: Prioritization of active antimalarials using structural interaction profile of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR)-triclosan derivatives.
abstract: An empirical relationship between the experimental inhibitory activities of triclosan derivatives and its computationally predicted Plasmodium falciparum enoyl-acyl carrier protein (ACP) reductase (PfENR) dock poses was developed to model activities of known antimalarials. A statistical model was developed using 57 triclosan derivatives with significant measures (r = 0.849, q(2) = 0.619, s = 0.481) and applied on structurally related and structurally diverse external datasets. A substructure-based search on ChEMBL malaria dataset (280 compounds) yielded only two molecules with significant docking energy, whereas eight active antimalarials (EC(50) < 100 nM, tested on 3D7 strain) with better predicted activities (pIC(50) ~ 7) from Open Access Malaria Box (400 compounds) were prioritized. Further, calculations on the structurally diverse rhodanine molecules (known PfENR inhibitors) distinguished actives (experimental IC(50) = 0.035 μM; predicted pIC(50) = 6.568) and inactives (experimental IC(50) = 50 μM; predicted pIC50 = -4.078), which showed that antimalarials possessing dock poses similar to experimental interaction profiles can be used as leads to test experimentally on enzyme assays.
authors.affiliation: a Department of Bioinformatics, Applied Botany Centre (ABC) , University School of Sciences, Gujarat University , Ahmedabad , India.
authors.forename: S P
authors.initials: SP
authors.lastname: Kumar
authors.forename: L B
authors.initials: LB
authors.lastname: George
authors.forename: Y T
authors.initials: YT
authors.lastname: Jasrai
authors.forename: H A
authors.initials: HA
authors.lastname: Pandya
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D015999:Multivariate Analysis; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D012236:Rhodanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014260:Triclosan / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D014260:Triclosan; D012236:Rhodanine; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Plasmodium falciparum enoyl-ACP reductase; antimalarials; docking; protein–ligand interaction profiles; triclosan derivatives