1 research outputs found
Calibration of 1,2,4-Triazole-3-Thione, an Original Zn-Binding Group of Metallo-β-Lactamase Inhibitors. Validation of a Polarizable MM/MD Potential by Quantum Chemistry
In the context of the SIBFA polarizable
molecular mechanics/dynamics (PMM/PMD) procedure, we report the calibration
and a series of validation tests for the 1,2,4-triazole-3-thione (TZT)
heterocycle. TZT acts as the chelating group of inhibitors of dizinc
metallo-β-lactamases (MBL), an emerging class of Zn-dependent
bacterial enzymes, which by cleaving the β-lactam bond of most
β-lactam antibiotics are responsible for the acquired resistance
of bacteria to these drugs. Such a study is indispensable prior to
performing PMD simulations of complexes of TZT-based inhibitors with
MBL’s, on account of the anchoring role of TZT in the dizinc
MBL recognition site. Calibration was done by comparisons to energy
decomposition analyses (EDA) of high-level <i>ab initio</i> QC computations of the TZT complexes with two probes: Zn(II), representative
of “soft” dications, and water, representative of dipolar
molecules. We performed distance variations of the approach of each
probe to each of the two TZT atoms involved in Zn ligation, the S
atom and the N atom <i>ortho</i> to it, so that each SIBFA
contribution matches its QC counterpart. Validations were obtained
by performing in- and out-of-plane angular variations of Zn(II) binding
in monoligated Zn(II)–TZT complexes. The most demanding part
of this study was then addressed. How well does Δ<i>E</i>(SIBFA) and its individual contributions compare to their QC counterparts
in the dizinc binding site of one MBL, L1, whose structure is known
from high-resolution X-ray crystallography? Six distinct complexes
were considered, namely each separate monozinc site, and the dizinc
site, whether ligated or unligated by TZT. Despite the large magnitude
of the interaction energies, in all six complexes Δ<i>E</i>(SIBFA) can match Δ<i>E</i>(QC) with relative errors
<2% and the proper balance of individual energy contributions.
The computations were extended to the dizinc site of another MBL,
VIM-2, and its complexes with two other TZT analogues. Δ<i>E</i>(SIBFA) faithfully reproduced Δ<i>E</i>(QC) in terms of magnitude, ranking of the three ligands, and trends
of the separate energy contributions. A preliminary extension to correlated
calculations is finally presented. All these validations should enable
a secure design of a diversity of TZT-containing MBL inhibitors: a
structurally and energetically correct anchoring of TZT should enable
all other inhibitor groups to in turn optimize their interactions
with the other target MBL residues