Prioritization of active antimalarials using structural interaction profile ofPlasmodium falciparumenoyl-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.

Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan

“…It may be that further engineering of triclosan by synthetic chemistry is necessary to improve delivery and half-life, but with regard to affinity triclosan is a viable non-toxic lead with a mechanism based on hitherto undiscovered selectivity. A number of triclosan analogs have already been synthesized 16 , 21 , demonstrating the ample opportunity for its improvement for use as an antimalarial.…”

“…Indeed, phenotypical, biochemical, structural evidence, and in silico simulations demonstrated that triclosan is a strong inhibitor of the P . falciparum enoyl reductase ( Pf ENR) 13 , 20 , 21 . However Yu et al .…”

“…Efforts to optimize the compound for use as an antimalarial showed no correlation between Pf ENR inhibition in vitro and triclosan’s activity against the living parasite 21 , 22 . Since it has been demonstrated that Pf ENR is important for the liver stage of the parasite, but not for the erythrocyte stage 22 , 23 , action against a different target must be responsible for triclosan’s inhibition of the growth of blood-stage P .…”

Identification of PfENR inhibitors: A hybrid structure‐based approach in conjunction with molecular dynamics simulations

“…In the past, Kumar et al have identified a class of rhodanine compounds as antimalarials using a docking and lead optimization approach. Consistent progress has been made in docking and inverse‐docking studies in discovering more potent Pf ENR inhibitors . Recently, a multi‐complex‐based pharmacophore modeling approach was used for the identification of structurally diverse ENR inhibitors .…”

“…Consistent progress has been made in docking and inverse-docking studies in discovering more potent PfENR inhibitors. 13 Recently, a multi-complex-based pharmacophore modeling approach was used for the identification of structurally diverse ENR inhibitors. 14 Although many studies have reported on the structure-based drug design, very few have focused on the exploration of the dynamic behavior of the ENR protein.…”