Insights into the bonding pattern for characterizing the open and closed state of the substrate-binding loop in...

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.

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.

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.