Background: The enzyme trans-enoyl-[acyl carrier protein] reductase (InhA) is a central
protein for the development of antitubercular drugs. This enzyme is the target for the pro-drug
isoniazid, which is catalyzed by the enzyme catalase-peroxidase (KatG) to become active.
Objective: Our goal here is to review the studies on InhA, starting with general aspects and focusing on
the recent structural studies, with emphasis on the crystallographic structures of complexes involving
InhA and inhibitors.
Method: We start with a literature review, and then we describe recent studies on InhA crystallographic
structures. We use this structural information to depict protein-ligand interactions. We also analyze the
structural basis for inhibition of InhA. Furthermore, we describe the application of computational
methods to predict binding affinity based on the crystallographic position of the ligands.
Results: Analysis of the structures in complex with inhibitors revealed the critical residues responsible
for the specificity against InhA. Most of the intermolecular interactions involve the hydrophobic residues
with two exceptions, the residues Ser 94 and Tyr 158. Examination of the interactions has shown
that many of the key residues for inhibitor binding were found in mutations of the InhA gene in the
isoniazid-resistant Mycobacterium tuberculosis. Computational prediction of the binding affinity for
InhA has indicated a moderate uphill relationship with experimental values.
Conclusion: Analysis of the structures involving InhA inhibitors shows that small modifications on
these molecules could modulate their inhibition, which may be used to design novel antitubercular
drugs specific for multidrug-resistant strains.