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

Abstract

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 ab initio 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 ortho 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 ΔE(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 ΔE(SIBFA) can match ΔE(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. ΔE(SIBFA) faithfully reproduced ΔE(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.

Calibration of the dianionic phosphate group: Validation on the recognition site of the homodimeric enzyme phosphoglucose isomerase

“…A new library of fragments with correlated multipoles and polarizabilities is presently being constructed (for preliminary results, see Refs. . The results of the following sections will serve as additional validations when this is achieved.…”

Spectrometric and computational studies of the binding of HIV-1 integrase inhibitors to viral DNA extremities

“…Improvements along these lines are being carried out presently, but with correlated multipoles and polarizabilities and on the basis of correlated EDA approaches. Each ligand of interest is probed in a diversity of positions by cationic and dipolar probes Kwapien et al, 2017) and using an automated procedure which, for each individual contribution, optimizes the relevant parameters by least-squares fit minimizing the error with respect to its QC counterpart (M. Devillers, et al, 2019, unpublished data).…”

“…In addition to handling the halobenzene interactions (El Hage et al, 2013, a further asset of SIBFA and related polarizable potentials (Bell et al, 2016) is the reliable handling of poly-ligated complexes of divalent cations (El Kwapien et al, 2017) and interactions involving "discrete" structural waters (De Courcy et al, 2010;Gresh et al, 2011). Such structural motives are also encountered in the intasome-INSTI complexes.…”

4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

“…The binding pose of these scaffolds in MBL binding site is conserved. The zinc-chelating power derives from their anionic nature: the delocalization of the negative charge between the 2-nitrogen and the non-ring sulfur may indicate the prevalence of a thiolate, rather than a thione, as supported by crystallographic evidence [40,41] and by recent works [34,46]. These observations led us to simulate the compounds as thiolates when docked in the MBLs.…”

“…With this in mind, we have selected the 4-amino-1,2,4-triazole-3-thione as the starting scaffold for the design and synthesis of a small library of new possible MBLIs [30][31][32][33][34][35]. The 14 compounds in the library were designed to extend their activity towards class A SBL KPC-2, while maintaining their affinity vs MBLs.…”