Peptide deformylase (PDF) has emerged as an important antibacterial drug target.
Considerable effort is being directed toward developing peptidic and non-peptidic inhibitors for this
metalloprotein. In this work, the known peptidic inhibitor BB-3497 and its various ionization and
tautomeric states are evaluated for their inhibition efficiency against PDF using a molecular mechanics
(MM) approach as well as a mixed quantum mechanics/molecular mechanics (QM/MM) approach,
with an aim to understand the interactions in the binding site. The evaluated Gibbs energies of binding
with the mixed QM/MM approach are shown to have the best predictive power. The experimental
pose is found to have the most negative Gibbs energy of binding, and also the smallest strain energy.
A quantum mechanical evaluation of the active site reveals the requirement of strong chelation by the ligand with the
metal ion. The investigated ligand chelates the metal ion through the two oxygens of its reverse hydroxamate moiety,
particularly the N-O- oxygen, forming strong covalent bonds with the metal ion, which is penta-coordinated. In the
uninhibited state, the metal ion is tetrahedrally coordinated, and hence chelation with the inhibitor is associated with an
increase of the metal ion coordination. Thus, the strong binding of the ligand at the binding site is accounted for.
Keywords: BB-3497 inhibitor, density functional theory, ESP charge analysis, molecular docking, MM, peptide deformylase
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