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

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.

In Silico Identification of JMJD3 Demethylase Inhibitors

“…First, the optimal orientation of metal–ligand complexes within a protein is not well reproduced by docking programs because of the complexity of the coordination geometries that transition metals can exploit. , Recent efforts have been devoted to the development of ad hoc programs for zinc-dependent proteins, as AutoDock4Zn and MpSDockZn, but their usage is limited to this class of proteins. Second, commonly used force field-based, empirical or knowledge-based scoring functions do not account for electronic effects, and consequently, they are not able to capture the nature of organometallic bonds, preventing a correct ranking of ligand poses. − More accurate binding energies from quantum mechanics (QM)-based scoring functions ,− seem to correlate with experimental data, but the application of these methodologies to high throughput screening is restricted by the computational cost. These limitations in the modeling of metal–ligand binding explain the general preference for experimental techniques compared to in silico studies for drug discovery of jumonji demethylases. − …”

Crystal Structures of Peptide Deformylase from Rice Pathogen Xanthomonas oryzae pv. oryzae in Complex with Substrate Peptides, Actinonin, and Fragment Chemical Compounds

“…Thus, far, no plant pathogen PDF structure has been determined. Structure-based inhibitor/drug screening study has been limited mostly to human pathogen targets. − The present study reports crystal structures of XoPDF as apo and in complexes with the substrates (methionine-alanine, MA, or methionine-alanine-serine, MAS), actinonin, and six fragment chemical compounds (FCCs) and systematic approaches to screen inhibitors against XoPDF using structural studies. The FCCs will provide useful information for the development of XoPDF inhibitors.…”