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Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo‐β‐lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry
Author(s) -
Antony Jens,
Piquemal JeanPhilip,
Gresh Nohad
Publication year - 2005
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.20245
Subject(s) - polarizable continuum model , chemistry , molecular mechanics , solvation , binding energy , intermolecular force , computational chemistry , carboxylate , quantum chemical , quantum chemistry , polarizability , force field (fiction) , captopril , computation , stereochemistry , molecular dynamics , molecule , quantum mechanics , physics , organic chemistry , mathematics , medicine , supramolecular chemistry , blood pressure , radiology , algorithm
Using the polarizable molecular mechanics method SIBFA, we have performed a search for the most stable binding modes of D‐ and L‐thiomandelate to a 104‐residue model of the metallo‐β‐lactamase from B. fragilis, an enzyme involved in the acquired resistance of bacteria to antibiotics. Energy balances taking into account solvation effects computed with a continuum reaction field procedure indicated the D‐isomer to be more stably bound than the L‐one, conform to the experimental result. The most stably bound complex has the S − ligand bridging monodentately the two Zn(II) cations and one carboxylate O − H‐bonded to the Asn193 side chain. We have validated the SIBFA energy results by performing additional SIBFA as well as quantum chemical (QC) calculations on small (88 atoms) model complexes extracted from the 104‐residue complexes, which include the residues involved in inhibitor binding. Computations were done in parallel using uncorrelated (HF) as well as correlated (DFT, LMP2, MP2) computations, and the comparisons extended to corresponding captopril complexes (Antony et al., J Comput Chem 2002, 23, 1281). The magnitudes of the SIBFA intermolecular interaction energies were found to correctly reproduce their QC counterparts and their trends for a total of twenty complexes. © 2005 Wiley Periodicals, Inc. J Comput Chem 11: 1131–1147, 2005