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Analysis of Enoyl‐Acyl Carrier Protein Reductase Structure and Interactions Yields an Efficient Virtual Screening Approach and Suggests a Potential Allosteric Site
Author(s) -
Ghattas Mohammad A.,
Mansour Ramez A.,
Atatreh Noor,
Bryce Richard A.
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12635
Subject(s) - druggability , virtual screening , allosteric regulation , acyl carrier protein , docking (animal) , inha , reductase , binding site , biochemistry , active site , protein–ligand docking , computational biology , biology , chemistry , stereochemistry , drug discovery , enzyme , biosynthesis , medicine , tuberculosis , nursing , isoniazid , pathology , gene
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 pfFabI. Analysis of the ligand–protein interactions of four enoyl‐acyl carrier protein reductases from different micro‐organisms (InhA, pfFabI, saFabI and ecFabI), 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.