Complexes of Thiomandelate and Captopril Mercaptocarboxylate Inhibitors to Metallo--lactamase by Polarizable Molecular Mechanics. Validation on Model Binding Sites by Quantum Chemistry JENS ANTONY, 1 JEAN-PHILIP PIQUEMAL, 2 NOHAD GRESH 3 1 Freie Universita ¨t Berlin, FB Mathematik und Informatik, Institut fu ¨r Mathematik II, AG Biocomputing, Arnimallee 2-6, D-14195 Berlin, Germany 2 Laboratory of Structural Biology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709 3 Laboratoire de Pharmacochimie Mole ´culaire et Cellulaire, FRE 2718 CNRS, IFR Biome ´dicale, 45, Rue des Saints-Pe `res, 75006 Paris, France Received 23 November 2004; Accepted 7 February 2005 DOI 10.1002/jcc.20245 Published online in Wiley InterScience (www.interscience.wiley.com). Abstract: 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--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 26: 1131–1147, 2005 Key words: metallo--lactamase; mercaptocarboxylate inhibitors; polarizable molecular mechanics; quantum chemistry; validation Introduction Metallo--lactamases are zinc enzymes inactivating -lactam an- tibiotics by hydrolyzing their endocyclic amide bond. 1,2 As a major source of bacterial resistance against these antibiotics, me- tallo--lactamases have continuously attracted the interest of mo- lecular modellers: molecular dynamics simulations of the entire protein 3 and quantum chemical calculations of active site com- plexes 4 have been performed, starting from structural information provided by X-ray crystallography. 1,2,5– 8 Frequently, experimen- tal studies are complemented by molecular modeling of inhibitor docking. 5,9 –14 Because resistance to -lactam antibiotics mediated by metal- lo--lactamases is an increasing problem, the study of inhibitors of metallo--lactamases is a very important task. We report on com- plexes of thiomandelic acid, a broad spectrum and reasonably potent inhibitor of metallo--lactamases. 15 Combination of 1 H, 15 N, and 113 Cd NMR, and 111m Cd perturbed angular correlation (PAC) of -ray spectroscopies showed that the inhibitor thiol binds to both metal ions. 14 Molecular modeling of complexes between Correspondence to: N. Gresh; e-mail: Nohad.gresh@univ-paris5.fr Contract/grant sponsor: Ligue Nationale Contre le Cancer (Comite ´ de Paris) This article includes Supplementary Material available from the authors upon request or via the Internet at http://www.interscience.wiley.com/ jpages/0192-8651/suppmat © 2005 Wiley Periodicals, Inc.