Docking Modes of BB-3497 into the PDF Active Site – A Comparison of the Pure MM and QM/MM Based Docking Strategies

Title:Docking Modes of BB-3497 into the PDF Active Site – A Comparison of the Pure MM and QM/MM Based Docking Strategies

Volume: 10 Issue: 4

Author(s): Tripti Kumari, Upasana Issar and Rita Kakkar

Affiliation:

Keywords: BB-3497 inhibitor, density functional theory, ESP charge analysis, molecular docking, MM, peptide deformylase (PDF), QM/MM.

Abstract: 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.

Cite this article as:

Kumari Tripti, Issar Upasana and Kakkar Rita, Docking Modes of BB-3497 into the PDF Active Site – A Comparison of the Pure MM and QM/MM Based Docking Strategies, Current Computer-Aided Drug Design 2014; 10 (4) . https://dx.doi.org/10.2174/157340991004150518145522