Analysis of Enoyl‐Acyl Carrier Protein Reductase Structure and Interactions Yields an Efficient Virtual Screening Approach and Suggests a Potential Allosteric Site

Abstract

Enoyl-acyl carrier protein reductases have an important role in fatty acid biosynthesis and are considered essential for bacterial and protozoal survival. Here, we perform a computational assessment of enoyl-acyl carrier protein reductase structures, providing insights for inhibitor design that we incorporate into a virtual screening approach. Firstly, we analyse 80 crystal structures of 16 different enoyl-acyl carrier protein reductases for their active site characteristics and druggability, finding these sites contain a readily druggable pocket, of varying size and shape. Interestingly, a high affinity, potentially allosteric site was identified for pfFabl. Analysis of the ligand-protein interactions of four enoyl-acyl carrier protein reductases from different micro-organisms (InhA, pfFabl, saFabl and ecFabl), involving 59 available crystal structures, found three commonly shared interactions; constraining these interactions in docking improved enrichment of enoyl-acyl carrier protein reductase virtual screens, by up to 60% in the top 3% of the ranked library. This docking protocol also improved pose prediction, decreasing the root-mean-square deviation to crystallographic pose by up to 75% on average. The binding site analysis and knowledge-based docking protocol presented here can potentially assist in the structure-based design of new enoyl-acyl carrier protein reductase inhibitors.

Computer-aided discovery of antimicrobial agents as potential enoyl acyl carrier protein reductase inhibitors

“…During docking, an interaction constraint that was previously identified to enhance the ENR virtual screening [6] was also applied here; to ensure that the key interaction with NADP + ribose will take place ( Figure 1B). …”

“…The Ushaped conformation of the fatty acyl substrate is guided by the third residue which is located close to the nicotinamide ring of NADP [5]. Our previous protein-ligand interaction study carried on saFabI crystal structures revealed that the proton donor Tyr is essential for the binding of the co-crystallized inhibitors; a hydrogen bonding between them was seen in all examined complexes [6]. The bound NADP + nicotinamide ring showed similar importance via making a π-π stacking interaction with the corresponding aromatic ring of the saFabI inhibitors.…”

“…The bound NADP + nicotinamide ring showed similar importance via making a π-π stacking interaction with the corresponding aromatic ring of the saFabI inhibitors. In the same study, it was revealed that constraining, particularly, the first key interaction during docking had a positive impact on the enrichment of the saFabI virtual screening as well as on the docking accuracy of the known saFabI inhibitors [6].…”

“…A docking protocol, that had been previously validated by our group [6], was also employed here against the saFabI enzyme. Using Pharmacophore Elucidation [9], a pharmacophoric feature was created for use in virtual screening; the pharmacophoric point was assigned based on the NADP + ribose 2-hydroxyl group (denoted as Acc2).…”

“…ENRs introduce themselves as potential targets for the development of new antibacterial agents [7] and employing the right drug design technique against them can eventually turn fruitful. In our current study, we employed a previously validated virtual screening approach [6] to target the saFabI-NADP + complex with a drug-like ligand library. Consequently, the topranked compounds were brought in and tested for their antibacterial activity against a panel of Gram-negative and Gram-positive bacterial strains.…”