Insights into the Bonding Pattern for Characterizing the Open and Closed State of the Substrate-Binding Loop in Mycobacterium Tuberculosis InhA

BACKGROUND: Direct InhA inhibitors, which interact with the substrate-binding loop (SBL) and order it into a closed state, are thought to be potential anti-multidrug-resistant tuberculosis molecules. Thus, developing parameters to distinguish between the open and closed state of SBL can help in screening the potent inhibitors with loop ordering properties. RESULTS: We report empirical parameters to differentiate the 'open' and 'closed' conformation of SBL by comprehensive ana-lysis of InhA crystal structures. The 'open' state of SBL was observed with intra- and inter-loop H-bonding within the residues pair, G205-G208 and L207-I105, respectively, while the 'closed' conformation is found with H-bonding within the residues pair: L207-E210 and A206-I105. Moreover, potent inhibitors (IC50, 5.3-5160 nM) are observed to make hydrophobic interactions with residues of SBL, particularly with A198 in the structures with closed state of SBL. CONCLUSION: The observed set of H-bonding pattern and hydrophobic contact with residues of SBL can be utilized as a filter to evaluate novel inhibitors for their SBL ordering properties and potencies using the molecular dynamic simulation in the virtual screening of direct InhA inhibitors.