Abstract

A correct representation of intermolecular interaction energies is necessary for reliable drug-receptor docking studies. While ab initio quantum chemistry with extended basis sets is the most accurate tool for that purpose, its use is precluded for very large molecular complexes. This constitutes the incentive for the development of accurate molecular mechanics potentials, in which the first-order electrostatic, and the second-order polarization energy contributions, are of essential importance. In this paper, we review the most important steps in the development of anisotropic, polarizable molecular mechanics (APMM) procedures. Among these, we illustrate validation tests of the ab initio-grounded, polarizable molecular mechanics potential, SIBFA (Sum of Interactions Between Fragments Ab initio computed). These are done by comparisons with parallel quantum-chemical (QC) results on representative multiply hydrogen-bonded complexes and polycoordinated complexes of one, or of two, divalent metal cations. For both kinds of complexes, the need to reproduce the non-additivity of the QC interaction energies is emphasized. One difficulty arises upon handling flexible molecules, due to the need to account simultaneously and consistently for the onset of inter- and intra-molecular polarization and charge-transfer effects. A new approach in the context of SIBFA was recently developed towards this aim, and tested in two cases of conformation-dependent cation-ligand interaction energies. The first relates to the complexes formed between the mecapto-carboxamide anion, an essential building-block of several Zn-metalloenzyme inhibitors, and Zn(II). The second relates to the complexes of the tetra-anionic pyrophosphate anion, a key building-block of ATP and GTP, with one or two divalent Zn(II) cations used as a probe. In the domain of applications, two recent studies are then presented. The first is the docking of the captopril drug to the active site of the binuclear Zn(II)- β-lactamase enzyme. The second is the complex of a non-hydrolyzable analog of ATP with the active site of a binuclear Mg(II)-dependent kinase. An extension to an open-shell cation, Cu(II), is finally presented. The encouraging results presented in this review show that APMM procedures could be used in large-scale studies of ligand and drug-receptor interactions.

Keywords: Intermolecular interactions, drug and ligand-receptor complexes, quantum chemistry, molecular mechanics, polarizability, anisotropy, nonadditivity