title: 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.
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain, 64141, United Arab Emirates.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Ghattas
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain, 64141, United Arab Emirates.
authors.forename: Ramez A
authors.initials: RA
authors.lastname: Mansour
authors.affiliation: College of Pharmacy, Al Ain University of Science and Technology, Al Ain, 64141, United Arab Emirates.
authors.forename: Noor
authors.initials: N
authors.lastname: Atatreh
authors.affiliation: Manchester Pharmacy School, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bryce
mesh_terms: D000495:Allosteric Site; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D008024:Ligands; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: FabI; InhA; allosteric site; antibacterial agents; antimalarial; docking; druggability; enoyl-acyl carrier protein reductase; pharmacophore; protein-ligand interaction analysis; virtual screening