Water molecules are the prime decision-makers in modern drug discovery as they play a vital role in macromolecular structure and their function. In the present study, to understand the effect of mutations on the fundamental, mechanistic, and conformational stability of Quinolone Binding pocket (QBP). In the present study, we carried out molecular dynamics simulation (MDS) on wild type and mutant forms of <i>Mtb</i> DNA gyrA complex with moxifloxacin.  This study identified a single water molecule, displaced from the catalytic site of DNA gyrase which prompted us to reinvestigate the thermodynamic parameters of five water molecules in the active site of the enzyme. Water thermodynamics calculations on WT and MTs of DNA gyrA revealed that water molecule, HOH201 was displaced due to lack of stable free energy (ΔG) value as compared to the remaining four bridged waters to the magnesium ion. However, it was noted that the thermodynamic properties of the four (HOH 202, 203, 209, 615) stable water molecules were also altered due to the effect of mutations. Thus, water thermodynamics calculations helped us to design a series of novel molecules that make strong DNA-gyrase binding by growing the parent Moxifloxacin with different hydrophobic substituents. The designed molecules provided meaningful insights into understanding the conformational stability of QBP around the solvated catalytic domain of gyrase and the importance of the H-bonded water network in maximizing the potency of molecules by taking advantage of direct binding to the gyrase protein.

Water network chemistry to exploit the nature of catalytic water molecules in <i>Mtb</i> DNA gyrase: A computational study to understand the binding mechanism of fluoroquinolones

ACS Spring Meeting 2021

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Water network chemistry to exploit the nature of catalytic water molecules in Mtb DNA gyrase: A computational study to understand the binding mechanism of fluoroquinolones