Dynamics of Plasmodium falciparum enoyl‐ACP reductase and implications on drug discovery

Abstract

Enoyl-acyl carrier protein reductase (ENR) is a crucial enzyme in the type II fatty acid synthesis pathway of many pathogens such as Plasmodium falciparum, the etiological agent of the most severe form of malaria. Because of its essential function of fatty acid double bond reduction and the absence of a human homologue, PfENR is an interesting drug target. Although extensive knowledge of the protein structure has been gathered over the last decade, comparatively little remains known about the dynamics of this crucial enzyme. Here, we perform extensive molecular dynamics simulations of tetrameric PfENR in different states of cofactor and ligand binding, and with a variety of different ligands bound. A pocket-volume analysis is also performed, and virtual screening is used to identify potential druggable hotspots. The implications of the results for future drug-discovery projects are discussed.

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

“…It is noteworthy that the extensive MD simulations conducted earlier on the PfENR-triclosan complex and its variants showed that the equilibration of all protein-ligand complexes occurred between 10 and 20 nanoseconds with a protein-RMSD value of 2.5 to 3.5 Å and a protein-RMSF value of less than 2.0 Å. 15 The results obtained in the present study were well within the benchmarked values reported earlier.…”

“…It is well documented in the literature that the PfENR protein attains stability between 10 and 20 nanoseconds of the simulation run. 15 Therefore, MD simulations of the 4 selected molecules along with the NAD-bound protein (ENR with cofactor only) were carried out for a duration of 20 nanoseconds. The stability of all the systems under investigation was evaluated by examining the RMSD and RMSF plots of both proteins and ligands.…”

“…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. 15 In general, MD is responsible for the flexibility of the protein-ligand complex, which is crucial for predicting the structural behavior of the system at the atomic level. For this purpose, a number of studies have been documented in the literature that use MD as a tool to study the functional behavior and interaction pattern of the receptor-ligand complexes.…”

In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors

“…Comprehensive computational and experimental studies elucidating both the structural (27, 32) and dynamic (34–38) nature of Pf ENR have been performed, with applications to drug discovery (39–42). With the advancement in computational and experimental technology, we can rationally and efficiently screen for novel drugs with a higher hit rate than the traditional and more expensive high-throughput library screens.…”

Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase

“…First, the formation of a ternary ENR-NAD + -TCL complex stabilizes a normally flexible substrate-binding loop and is postulated to be the slowest step in the formation of the enzyme-inhibitor complex. 45–49 Second, once bound, TCL is stabilized via π-stacking interactions between the TCL phenolic ring and the NAD + nicotinamide ring. 40 Indeed, kinetic studies have demonstrated that the IC 50 value of TCL improves with NAD + preincubation (i.e., TCL is an uncompetitive inhibitor with respect to varying NAD + concentrations).…”